Benzofuran derivatives useful as inhibitors of mammalian leukotriene biosynthesis

ABSTRACT

Benzofuran derivatives, pharmaceutical compositions and methods of treatment are disclosed. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders, inflammation. The compounds ar also useful as analgesics and as cytoprotective agents.

CROSS REFERENCE

This is a CIP of application U S. Ser. No. 146,882 filed Jan. 22, 1988,titled "Benzofuran Derivatives" in the names of Belanger et al. nowabandoned, which is a coninuation of application U.S. Ser. No. 931,751,filed Nov. 17, 1986, abandoned, which is a continuation of applicationU.S. Ser. No. 741,379, filed June 7, 1985, abandoned, which is a CIP ofapplication U.S. Ser. No. 622,372, filed June 20, 1984, abandoned.

BACKGROUND OF THE INVENTION

This invention involves certain benzofuran derivatives. These compoundsare useful as inhibitors of mammalian leukotriene biosynthesis. As such,these compounds are useful therapeutic agents for treating allergicconditions, asthma, cardiovascular disorders and inflammation. Thecompounds are also useful as analgesics and as cytoprotective agents.

The leukotrienes are a novel group of biologically active mediatorsderived from arachidonic acid through the action of lipoxygenase enzymesystems. There are two groups of leukotrienes derived from the commonunstable precursor Leukotriene A₄. The first of these are thepeptido-lipid leukotrienes, the most important being Leukotrienes C₄ andD₄. These compounds collectively account for the biologically activematerial known as the slow reacting substance of anaphylaxis.

The leukotrienes are potent smooth muscle contracting agents,particularly on respiratory smooth muscle but also on other tissues(e.g. gall bladder). In addition, they promote mucous production,modulate vascular permeability changes and are potent inflammatoryagents in human skin. The most important compound in the second group ofleukotrienes is Leukotriene B₄, a dihydroxy fatty acid. This compound isa potent chemotactic agent for neutrophils and eosinophils and inaddition, may modulate a number of other functions of these cells. Italso affects other cell types such as lymphocytes and, for example, maymodulate the action of T-suppressor cells and natural killer cells. Wheninjected invivo, in addition to promoting the accumulation ofleukocytes, Leukotriene B₄ is also a potent hyperalgesic agent and canmodulate vascular permeability changes through a neutrophil dependentmechanism. Both groups of leukotrienes are formed following oxygenationof arachidonic acid through the action of a 5-lipoxygenase enzyme. Seefor example, D. M. Bailey et al., Ann. Rpts. Med. Chem. 17 203 (1982).

The leukotrienes are potent spasmogens of human trachea, bronchus andlung parenchymal strips, and when administered to normal volunteers asaerosols are 3,800 times more potent that histamine at inducing a 50%decrease in air flow at 30% of vital capacity. They mediate increases invascular permeability in animals and promote mucous production in humanbronchial explants. In addition, Leukotriene B₄ may also mediate mucousproduction and could be an important mediator of neutrophil andeosinophil accumulation in asthmatic lungs. 5-lipoxygenase products arealso thought to be regulators of mast cell degranulation and recentstudies with human lung mast cells have suggested that 5-lipoxygenaseinhibitors, but not corticosteroids, may suppress antigen-induced mastcell degranulation. In vitro studies have shown that antigen challengeof human lung results in the release of leukotrienes and in additionpurified human mast cells can produce substantial amount ofleukotrienes. There is therefore good evidence that leukotrienes areimportant mediators of human asthma. 5-lipoxygenase inhibitors wouldtherefore be a new class of drugs for the treatment of asthma. See, forexample, B. Samuelsson, Science 220, 568-575 (1983).

Psoriasis is a human skin disease which affects between two and sixpercent of the population. There is no adeguate therapy for psoriasisand related skin conditions. The evidence for leukotriene involvement inthese diseases is as follows. One of the earliest events in thedevelopment of prepapillary lesions is the recruitment of leukocytes tothe skin site. Injection of Leukotriene B₄ into human skin results in apronounced neutrophil accumulation. There are gross abnormalities inarachidonic acid metabolism in human psoriatic skin. In particular,highly elevated levels of free arachidonic acid can be measured as wellas large amounts of lipoxygenase products. Leukotriene B₄ has beendetected in psoriatic lesions, but not in uninvolved skin, inbiologically significant amounts.

Leukotrienes can be measured in nasal washings from patients withallergic rhinitis and are greatly elevated following antigen challenge.Leukotrienes may mediate this disease through their ability to regulatemast cell degranulation, by modulating mucous production and mucocillaryclearance and by mediating the accumulation of inflammatory leukocytes.

Leukotrienes can also mediate other diseases. These include atopicdermatitis, gouty arthritis, and gall bladder spasms. In addition, theymay have a role in cardiovascular disease because leukotrienes C₄ and D₄act as coronary and cerebral arterial vasoconstrictors and thesecompounds may also have negative inotropic effects on the myocardium. Inaddition, the leukotrienes are important mediators of inflammatorydiseases through their ability to modulate leukocyte and lymphocytefunction.

SUMMARY OF THE INVENTION

It has now been discovered that certain substituted benzofurans andbenzothiofurans of Formula I are effective inhibitors of leukotrienebiosynthesis. Thus, these compounds are useful therapeutic agents fortreating conditions such as asthma, allergies, cardiovascular disorderssuch as angina and inflammation, for amelioration of skin diseases likepsoriasis and atopic eczema, and as cytoprotective agents.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are compounds of the formula:##STR1## wherein: each R¹ is independently hydrogen or C₁ to C₆ alkyl;

R² is hydrogen, C₁ to C₆ alkyl, --(CH₂)_(n) -Het-Y, or ##STR2## R³ ishydroxyl, ##STR3## OCOCH₂ CH₂ COOH, OSO₃ H, or OPO₃ H₂ ; each R⁴ isindependently C₁ to C₆ alkyl;

each R⁵ is independently H, C₁ to C₆ alkyl, or both R⁵ s join to form a5- or 6-membered ring with the N to which they are attached;

Het is a heterocyclic group selected from pyridine, pyrazine,pyrimidine, oxazole, pyrazole, oxadiazole, tetrazole, guinoline,thiophene, furan, pyrrole, thiazole, thiadiazole, or imidazole;

X is O, S, SO, SO₂ ;

Y, Y¹, Y², Y³, Y₄ and Z are each independently H, halogen, OH, C₁ to C₆alkyl, C₂ to C₆ alkenyl, --COOR¹, --COR¹, nitro, C₁ to C₆ alkoxy, C₁ toC₆ alkylthio, --CH₂ SR¹, OCH₂ CO₂ R¹, ##STR4## and each n isindependently 0 to 10; with the provisos that:

(a) not all of R¹, R², Y, Y¹, Y², Y³, Y₄, and Z are simultaneously H;

(b) when up to 2 of R¹, R²,Y, Y¹, and Z are C₁ to

C₂ alkyl, and the others of R¹, R²,Y, Y¹, and Z are H, then R³ is notOH; and

(c) when n in ##STR5## is O and one of R³, Y, Y¹ or Z is OH, then R¹ isnot H or C₁ to C₂ alkyl;

and the pharmaceutically acceptable salts thereof.

Unless otherwise indicated, the alkyl groups or alkyl portions of othergroups may be straight chain, branched or cyclic or may contain bothstraight chain or branched and cyclic portions

By halogen is meant fluorine, chlorine, bromine or iodine.

The heterocycles of --NR⁵ R⁵ when R⁵ R⁵ are joined include pyrrolidine,piperidine, and morpholine.

Preferred compounds of the present invention are compounds of Formula Ias defined above, wherein:

each R¹ is C₁ to C₃ alkyl;

R² is hydrogen, C₁ to C₃ alkyl, ##STR6## or --(CH₂)_(n) -Het-Y; R³ ishydroxyl, ##STR7## OCOCH₂ CH₂ COOH, OSO³ H, or OPO³ H₂ ; each R₄ isindependently C₁ to C₃ alkyl;

Het is heterocyclic group selected from pyridine, quinoline, thiazole,thiadiazole, or imidazole;

X is 0 or S;

Y, Y¹, Y²,Y³,Y₄,and Z are each independently H, halogen C₁ to C₃ alkyl,C₂ or C₃ alkenyl, --COOR¹, COR¹, C₁ to C₃ alkoxy, C₁ to C₃ alkylthio,--CH₂ SR¹, ##STR8## Y² is also OCH₂ CO₂ R¹ ; each n is independently 0to ₄ ;

and the pharmaceutically acceptable salts thereof.

More preferred compounds of the present invention are compounds of theFormula I as defined above, wherein:

each R¹ is methyl;

R² is hydrogen, ##STR9## or --CH₂ --Het--Y; R³ is 4-hydroxyl, 4-OSO₃ H,or 4-OPO₃ H₂ ;

Het is a pyridine;

n =1 or 2;

X is O; and

Y, Y¹, Y²,Y³,Y⁴,and Z are each independently H, fluorine, chlorine,methyl, propyl, allyl, --COOR¹, --COR¹, methoxy, methylthio, --CH² SR¹,or --CF³ ;

and the pharmaceutically acceptable salts thereof.

Most preferred compounds of the present invention are compounds ofFormula I as defined above, wherein:

each R¹ is methyl;

R² is ##STR10## R³ is 4-hydroxyl, 4-OPO₃ H₂,or 4 OSO₃ H; Het is apyridine;

X is O; and

Y, Y¹, Y²,Y³,Y⁴,and Z are each independently H, fluorine, chlorine,propyl, allyl, methoxy, or CH₂ SR¹ ;

and the pharmaceutically acceptable salts thereof.

Other most preferred compounds of the present invention are compounds ofFormula I as defined above, wherein:

each R¹ is methyl;

R² is hydrogen;

R³ is 4-hydroxyl, 4 OPO₃ H₂,or 4-OSO₃ H;

Het is a pyridine;

X is O; and

Y, Y¹, Y²,Y³,Y⁴,and Z are each independently H, fluorine, chlorine,propyl, allyl, methoxy, or CH² SR¹ ; and the pharmaceutically acceptablesalts thereof.

Still other most preferred compounds of the present invention arecompounds of Formula I as defined above, wherein:

each R¹ is methyl;

R² is --CH₂ Het--Y;

R³ is 4 hydroxyl, 4-OPO₃ H₂,or 4 OSO₃ H;

Het is a pyridine;

X is 0; and

Y, Y¹, Y²,Y³,Y₄,and Z are each independently H, fluorine, chlorine,propyl, allyl, methoxy, or CH² SR¹ ;

and the pharmaceutically acceptable salts thereof.

Some of the compounds described herein contain one or more centers ofasymmetry and may thus give rise to diastereoisomers and optioalisomers. The present invention is meant to comprehend such possiblediastereoisomers as well as their racemic and resolved optically activeforms.

Tables 1-4 list compounds of Formula I of this invention.

    TABLE 1      COMPOUNDS OF FORMULA I R.sup.1 R.sup.2 R.sup.3 X Y Y.sup.1 Y.sup.2     Y.sup.3 Y.sup.4       2 CH.sub.3 H 4-OCO.sub.2 CH.sub.3 O H H -- -- -- 4 CH.sub.3 H 4-OH O     5-allyl H -- -- -- 5 CH.sub.3 H 4-OH O 5-propyl H -- -- -- 6 CH.sub.3 H     4-OCO.sub.2 CH.sub.3 O 5-propyl H -- -- -- 7 CH.sub.3 H 4-OH O 7-propyl     H -- -- -- 8 CH.sub.3 C.sub.2 H.sub.5 4-OH O 5-allyl H -- -- -- 9     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H H H H 10 C.sub.3     H.sub.7 H 4-OH O H H -- -- -- 11 C.sub.3 H.sub.7 H 4-Oallyl O H H -- --     -- 12 C.sub.3 H.sub.7 H 4-OH O 5-allyl H -- -- -- 13 C.sub.6 H.sub.5 H     4-OH O H H -- -- -- 14 CH.sub.3 CH.sub.2 4-pyridyl 4-OH O 5-propyl H H H     H 15 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 5-OH O 6-OH H H H H 16 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H 4-OH H H 17 CH.sub.3 CH.sub.2     C.sub.6      H.sub.5 4-OH O 5-propyl H 4-OCH.sub.3 H H 21 CH.sub.3 H 5,6-OCH.sub.2 O     O H H -- -- -- 22 CH.sub.3 H 4-OCH.sub.3 O 7-propyl H -- -- -- 24     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OCO.sub.2 CH.sub.3 O 5-propyl H 4-OH     H H 25 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OCO.sub.2 CH.sub.3 O 5-propyl     H 4-OCH.sub.3 H H 26 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl     7-F H H H 27 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-OH     H H 28 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-OCH.sub.3     H H 29 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-F H H 30     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-Cl H H 31     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-N(CH.sub.3)2 H H     32 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H 4-F H H 33     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H 4-Cl H H 34 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H 4-N(CH.sub.3).sub.2 H H 35     C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H H H H 36     C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-F H H 37     C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-OH H H 38     C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F 4-OCH.sub.3     H H 39 C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-F     4-N(CH.sub.3).sub.2 H H 40 C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5 4-OH     O 5-propyl H 4-OCH.sub.3 H H 41 C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5     4-OH O 5-propyl H 4-OH H H 42 C.sub.3 H.sub.7 CH.sub.2 C.sub.6 H.sub.5     5-OH O 6-OH H 4-OCH.sub.3 H H 43 C.sub.3 H.sub.7 CH.sub.2 C.sub.6     H.sub.5 5-OH O 6-OH H 4-F H H 44 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 5-OH     O H H 4-OCH.sub.3 H H 45 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 6-OH O     5-propyl H 4-OCH.sub.3 H H 46 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-allyl H 4-OCH.sub.3 H H 48 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-CH.sub.2 SCH.sub.3 H 4-OCH.sub.3 H H 49 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH O 5-CH.sub.2 OCH.sub.3 H H H H 50 CH.sub.3 CH.sub.2     6-quinoline 4-OH O 5-propyl H H H H 51 CH.sub.3 CH.sub.2 3-furan 4-OH O     5-propyl H H H H 52 CH.sub.3 CH.sub.2 3-thiophene 4-OH O 5-propyl H H H     H 53 CH.sub.3 CH.sub.2 3-pyrrole 4-OH O 5-propyl H H H H 54 CH.sub.3     CH.sub.2 2-pyridyl 4-OH O 5-propyl H H H H 55 CH.sub.3 CH.sub.2      --thiadiazole 4-OH O 5-propyl H H H H 56 CH.sub.3 CH.sub.2 thiazole     4-OH O 5-propyl H H H H 57 CH.sub.3 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5     4-OH O 5-propyl H 4-OCH.sub.3 H H 58 CH.sub.3 C.sub.6 H.sub.5 4-OH O     5-propyl H 4-OCH.sub.3 H H 59 CH.sub.3 C.sub.6 H.sub.5 4-OH O 5-propyl H     4-OH H H 60 CH.sub.3 C.sub.6 H.sub.5 4-OH O 5-propyl H 4-F H H 61     CH.sub.3 C.sub.6 H.sub.5 4-OH S 5-propyl H 4-OCH.sub.3 H H 62 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH S 5-propyl H H H H 63 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH S 5-propyl H 4-OCH.sub.3 H H 64 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH S 5-propyl 7-F 4-OCH.sub.3 H H 65 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH S 5-propyl 7-F 4-F H H 66 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 5-OH S 6-OH H 4-OCH.sub.3 H H 67 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH SO 5-propyl 7-F 4-OCH.sub.3 H H 68 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH SO.sub.2 5-propyl 7-F 4-OCH.sub.3 H H 69 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-COCH.sub.3 7-F 4-OCH.sub.3 H H 70     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-COCH.sub.3 7-F 4-OCH.sub.3 H     H 72 CH.sub.3 CCH.sub.2 C.sub.6 H.sub.5 4-OH O H H 4-Cl H H 73 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl 4-OCH.sub.3 3-CHO H 74     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl 4-Br H H 75     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H 4-Cl H H 76 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 5-OH O 4-propyl 7-Cl 4-F H H 77 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OAc O 5-propyl 7-Cl 4-OAc H H 78 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OAc O 5-propyl H 4-OH H H 79 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 5-OH O 4-propyl H 4-OH H H 80 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 5-OH O H H 4-OH H H 81 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     7-OH O H H 4-OCH.sub.3 H H 82 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-Oallyl     O H H 4-OCH.sub.3 H H 84 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OAc O     5-propyl 7-Cl 4-OCH.sub.3 H H 85 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OAc     O 5-propyl 7-F 4-OCH.sub.3 H H 86 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OCO.sub.2 CHClCH.sub.3 O 5-propyl 7-Cl 4-OCH.sub.3 H H 87 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OCO.sub.2 CH.sub.3 O 5-propyl 7-F 4-OCH.sub.3     H H 88 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OCO.sub.2 CH.sub.3 O 5-propyl     7-Cl 4-OCH.sub.3 H H 89 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-propyl 7-Br 4-OCH.sub.3 H H 90 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH     O 5-propyl 7-Cl 4-OCH.sub.3 H H 91 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OH O 5-allyl H 4-OCH.sub.3 H H 92 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OH O H H 4-OCH.sub.3 H H 93 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     7-propyl H 4-OCH.sub.3 H H 94 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-propyl 7-CH.sub.3 4-OCH.sub.3 H H 95 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OH O 5-propyl 7-Pr 4-OCH.sub.3 H H 96 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH O 5-Cl 7-Pr 4-OCH.sub.3 H H 97 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OPO.sub.3 H.sub.2 O 5-propyl 7-Cl 4-OCH.sub.3 H H 98 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H O 5-propyl     7-F 4-OCH.sub.3 H H 99 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OCOCH.sub.2     CH.sub.2 CO.sub.2 H O 5-propyl 7-Cl 4-OCH.sub.3 H H 100 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 5-OAc O 4-propyl H 4-OCH.sub.3 H H 101 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 5-OCO.sub.2 CH.sub.3 O 4-propyl H 4-OCH.sub.3 H     H 102 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 5-OH O 4-propyl H 4-OCH.sub.3 H     H 103 CH.sub.3 CH.sub.2 C.sub.6      H.sub.5 4-OAc O 5-propyl 7-Cl 4-OCH.sub.2 CO.sub.2 Et H H 105 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl 4-OCH.sub.2 CO.sub.2 H H H     107 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl H H H H 108     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl H H H 109     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl 4-OH H H 110     CH.sub.3 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 4-OAc O H H 4-OCH.sub.3 H H     111 CH.sub.3 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 4-OH O H H 4-OCH.sub.3 H     H 112 CH.sub.3 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl     4-OCH.sub.3 H H 113 CH.sub.3 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-propyl H 4-OCH.sub.3 H H 114 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OSO.sub.3 H O 5-propyl 7-Cl 4-OCH.sub.3 H H 115 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl 4-SCH.sub.3 H H 116 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O CH.sub.2 SCH.sub.3 7-Cl 4-OCH.sub.3 H H     117 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O CH.sub.2 SOCH.sub.3 7-Cl     4-OCH.sub.3 H H 118 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O CH.sub.2     SO.sub.2 CH.sub.3 7-Cl 4-OCH.sub.3 H H 119 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH O CH.sub.2 OCH.sub.3 7-Cl 4-OCH.sub.3 H H 120 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OSO.sub.3 H O CH.sub.2 SCH.sub.3 7-Cl     4-OCH.sub.3 H H 121 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OCOCH.sub.2     CH.sub.2 CO.sub.2 H O CH.sub.2 SCH.sub.3 7-Cl 4-OCH.sub.3 H H 122     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OPO.sub.3 H.sub.2 O CH.sub.2     SCH.sub.3 7-Cl 4-OCH.sub.3 H H 123 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OPO.sub.3 H.sub.2 O CH.sub.2 SO.sub.2 CH.sub.3 7-Cl 4-OCH.sub.3 H H     124 CH.sub.3 CH.sub. 2 C.sub.6 H.sub.5 4-OH O CH.sub.2 SCH.sub.3 7-F     4-OCH.sub.3 H H 125 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O CH.sub.2     SOCH.sub.3 7-F 4-OCH.sub.3 H H 126 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OH O CH.sub.2 SO.sub.2 CH.sub.3 7-F 4-OCH.sub.3 H H 127 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O CH.sub.2 OCH.sub.3 7-F 4-OCH.sub.3 H H     128 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OSO.sub.3 H O CH.sub.2 SCH.sub.3     7-F 4-OCH.sub.3 H H 129 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OCOCH.sub.2     CH.sub.2 CO.sub.2 H O CH.sub.2 SCH.sub.3 7-F 4-OCH.sub.3 H H 130     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OPO.sub.3 H.sub.2 O CH.sub.2     SCH.sub.3 7-F 4-OCH.sub.3 H H 131 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OPO.sub.3 H.sub.2 O CH.sub.2 SO.sub.2 CH.sub.3 7-F 4-OCH.sub.3 H H 132     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O CH.sub.2 SCH.sub.3 7-Pr     4-OCH.sub.3 H H 133 CH.sub.3 CH.sub.2 C.sub. 6 H.sub.5 4-OH O CH.sub.2     SOCH.sub.3 7-Pr 4-OCH.sub.3 H H 134 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OH O CH.sub.2 SO.sub.2 CH.sub.3 7-Pr 4-OCH.sub.3 H H 135 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O CH.sub.2 OCH.sub.3 7-Pr 4-OCH.sub.3 H H     136 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OSO.sub.3 H O CH.sub.2 SCH.sub.3     7-Pr 4-OCH.sub.3 H H 137 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OCOCH.sub.2     CH.sub.2 CO.sub.2 H O CH.sub.2 SCH.sub.3 7-Pr 4-OCH.sub.3 H H 138     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OPO.sub.3 H.sub.2 O CH.sub.2     SCH.sub.3 7-Pr 4-OCH.sub.3 H H 139 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5     4-OPO.sub.3 H.sub.2 O CH.sub.2 SO.sub.2 CH.sub.3 7-Pr 4-OCH.sub.3 H H     140 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-CO.sub.2 H     4-OCH.sub.3 H H 141 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl     7-Cl 4-CO.sub.2 H H H 142 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-propyl 7-F 4-CO.sub.2 H H H 143 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH     O 5-CH.sub.2 CHOHCH.sub.2 OH 7-Cl 4-CO.sub.2 H H H 144 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH O 5-CH.sub.2 CHOHCH.sub.2 OH 7-F 4-CO.sub.2 H H H     145 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-CH.sub.2 CHOHCH.sub.3     7-Cl 4-CO.sub.2 H H H 146 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-CH.sub.2 CHOHCH.sub.3 7-F 4-CO.sub.2 H H H 147 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH O 5-propyl 7-SO.sub.3 H 4-OCH.sub.3 H H 148     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-CH.sub.2 CH.sub.2 OH 7-Cl     4-CO.sub.2 H H H 149 CH.sub.3 CH.sub.2 C.sub.6      H.sub.5 4-OH O 5-C(CH.sub.3).sub.3 7-Cl 4-CO.sub.2 H H H 150 CH.sub.3     CH.sub.2 C.sub.6      H.sub.5 4-OH O 5-C(CH.sub.3).sub.3 7-CH.sub.3 4-CO.sub.2 H H H 151     CH.sub.3 CH.sub.2 tetrazol 4-OH O 5-propyl 7-Cl 4-CH.sub.3 O H H 152     CH.sub.3 CH.sub.2 tetrazol 4-OH O 5-propyl 7-CH.sub.3 4-CH.sub.3 O H H     153 CH.sub.3 CH.sub.2 tetrazol 4-OH O 5-propyl 7-F 4-CH.sub.3 O H H 154     CH.sub.3 CH.sub.2 tetrazol 4-OH O 5-propyl H 4-CH.sub.3 O H H 155     CH.sub.3 CH.sub.2 tetrazol 4-OH O 5-propyl 7-Pr 4-CH.sub.3 O H H 156     CH.sub.3 CH.sub.2 tetrazol 5-OH O 5-propyl 7-Pr 4-CH.sub.3 O H H 157     CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O H H H H H 158 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OAc O H H H H H 159 CH(CH.sub.3).sub.2 CH.sub.2     C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl 4-CH.sub.3      O H H 160 CH(CH.sub.3).sub.2 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl     7-Cl 4-CH.sub.3 O H H 161 CH(CH.sub.3).sub.2 H 5-OH O H H -- -- -- 162     CH(CH.sub.3).sub.2 H 4-OH O H H -- -- -- 163 CH.sub.3 H 4-OH O 5-propyl     7-Cl -- -- -- 164 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O H 7-Cl     4-CH.sub. 3 O H H 165 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-C.sub.4     H.sub.9 7-Cl 4-CH.sub.3 O H H 166 H CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-propyl 7-Cl 4-CH.sub.3 O H H 167 Propyl CH.sub.2 C.sub.6 H.sub.5 4-OH     O 5-propyl 7-Cl 4-CH.sub.3 O H H 168 CH.sub.3 CH.sub.3 CH--C.sub.6     H.sub.5 4-OH O 5-propyl 7-Cl 4-CH.sub.3 O H H 169 CH.sub.3 C.sub.7     H.sub.15 4-OH O 5-propyl H -- -- -- 170 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH O 5-propyl 6-OMe 4-CH.sub.3 O H H 171 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH S 5-propyl 7-Cl 4-CH.sub.3 O H H 172 CH.sub.3     C.sub.6 H.sub.5 4-OH O 5-propyl 7-Cl H H H 173 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH O 5-Cl 7-Cl 4-CH.sub.3 O H H 174 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH O 5-propyl 7-Cl 4-Cl H H 175 CH.sub.3 CH.sub.2 C.sub.6     H.sub.5 4-OH O 5-propyl 7-Cl 2-CH.sub.3 O 4-CH.sub.3 O H 176 CH.sub.3     CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-propyl 7-CH.sub.2 NMe.sub.2 4-CH.sub.3     O H H 177 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-CH.sub.2 NMe.sub.2     7-Cl 4-CH.sub.3 O H H 178 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-Me     7-Cl 4-CH.sub.3 O H H 179 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O     5-allyl 7-Cl 4-CH.sub.3 O H H 180 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH     O 5-(CH.sub.2).sub.3 OH 7-Cl 4-CH.sub.3 O H H 181 CH.sub.3 CH.sub.2     C.sub.6 H.sub.5 4-OH O 5-(CH.sub.2).sub.2 CO.sub.2 H 7-Cl 4-CH.sub.3 O H     H 182 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 4-OH O 5-EtO 7-Cl 4-CH.sub.3 O H     H

                                      TABLE 2                                     __________________________________________________________________________    Perferred Compounds of Formula I                                              R.sup.1   R.sup.2  R.sup.3    X Y          Y.sup.1                                                                            Y.sup.2 Y.sup.3                                                                            Y.sup.4          __________________________________________________________________________    5   CH.sub.3                                                                            H        4-OH       O 5-propyl   H    --      --   --               8   CH.sub.3                                                                            C.sub.2 H.sub.5                                                                        4-OH       O 5-allyl    H    --      --   --               14  CH.sub.3                                                                            CH.sub.2 4-pyridyl                                                                     4-OH       O 5-propyl   H    H       H    H                15  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OH       O 6-OH       H    H       H    H                16  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    4-OH    H    H                17  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    4-OCH.sub.3                                                                           H    H                26  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-F  H       H    H                27  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-F  4-OH    H    H                28  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-F  4-OCH.sub.3                                                                           H    H                29  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-F  4-F     H    H                30  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-F  4-Cl    H    H                32  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    4-F     H    H                33  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    4-Cl    H    H                34  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    4-N(CH.sub.3).sub.2                                                                   H    H                35  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    H       H    H                39  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-F  4-N(CH.sub.3).sub.2                                                                   H    H                44  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OH       O H          H    4-OCH.sub.3                                                                           H    H                46  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-allyl    H    4-OCH.sub.3                                                                           H    H                48  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-CH.sub.2 SCH.sub.3                                                                     H    4-OCH.sub.3                                                                           H    H                49  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-CH.sub.2 OCH.sub.3                                                                     H    H       H    H                50  CH.sub.3                                                                            CH.sub.2 6-quinoline                                                                   4-OH       O 5-propyl   H    H       H    H                51  CH.sub.3                                                                            CH.sub.2 4-OHuran   O 5-propyl   H    H       H    H                52  CH.sub.3                                                                            CH.sub.2 3-thiophene                                                                   4-OH       O 5-propyl   H    H       H    H                53  CH.sub.3                                                                            CH.sub.2 3-pyrrole                                                                     4-OH       O 5-propyl   H    H       H    H                54  CH.sub.3                                                                            CH.sub.2 2-pyridyl                                                                     4-OH       O 5-propyl   H    H       H    H                55  CH.sub.3                                                                            CH.sub.2 --thiadiazole                                                                 4-OH       O 5-propyl   H    H       H    H                56  CH.sub.3                                                                            CH.sub.2 thiazole                                                                      4-OH       O 5-propyl   H    H       H    H                73  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-OCH.sub.3                                                                           3-CHO                                                                              H                74  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-Br    H    H                75  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    4-Cl    H    H                76  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OH       O 4-propyl   7-Cl 4-F     H    H                77  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OAc      O 5-propyl   7-Cl 4-OAc   H    H                78  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OAc      O 5-propyl   H    4-OH    H    H                79  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OH       O 4-propyl   H    4-OH    H    H                80  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OH       O H          H    4-OH    H    H                81  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               7-OH       O H          H    4-OCH.sub.3                                                                           H    H                82  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-Oallyl   O H          H    4-OCH.sub.3                                                                           H    H                84  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OAc      O 5-propyl   7-Cl 4-OCH.sub.3                                                                           H    H                85  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OAc      O 5-propyl   7-F  4-OCH.sub.3                                                                           H    H                86  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OCO.sub.2 CHClCH.sub.3                                                                 O 5-propyl   7-Cl 4-OCH.sub.3                                                                           H    H                87  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OCO.sub.2 CH.sub.3                                                                     O 5-propyl   7-F  4-OCH.sub.3                                                                           H    H                88  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OCO.sub.2 CH.sub.3                                                                     O 5-propyl   7-Cl 4-OCH.sub.3                                                                           H    H                89  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Br 4-OCH.sub.3                                                                           H    H                90  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-CH.sub.3 O                                                                          H    H                91  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-allyl    H    4-OCH.sub.3                                                                           H    H                92  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O H          H    4-OCH.sub.3                                                                           H    H                93  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 7-propyl   H    4-OCH.sub.3                                                                           H    H                94  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-CH.sub.3                                                                         4-OCH.sub.3                                                                           H    H                95  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Pr 4-OCH.sub.3                                                                           H    H                96  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-Cl       7-Pr 4-OCH.sub.3                                                                           H    H                97  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OPO.sub.3 H.sub.2                                                                      O 5-propyl   7-Cl 4-OCH.sub.3                                                                           H    H                98  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O 5-propyl   7-F  4-OCH.sub.3                                                                           H    H                99  CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O 5-propyl   7-Cl 4-OCH.sub.3                                                                           H    H                100 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OAc      O 4-propyl   H    4-OCH.sub.3                                                                           H    H                101 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OCO.sub.2 CH.sub.3                                                                     O 4-propyl   H    4-OCH.sub.3                                                                           H    H                102 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               5-OH       O 4-propyl   H    4-OCH.sub.3                                                                           H    H                103 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OAc      O 5-propyl   7-Cl 4-OCH.sub.2 CO.sub.2                                                                  Ht   H                105 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-OCH.sub.2 CO.sub.2                                                                  H    H                107 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   H    H       H    H                108 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl H       H    H                110 CH.sub.3                                                                            CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                      4-OAc      O H          H    4-OCH.sub.3                                                                           H    H                111 CH.sub.3                                                                            CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                      4-OH       O H          H    4-OCH.sub.3                                                                           H    H                112 CH.sub.3                                                                            CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                      4-OH       O 5-propyl   7-Cl 4-OCH.sub.3                                                                           H    H                113 CH.sub.3                                                                            CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                      4-OH       O 5-propyl   H    4-OCH.sub.3                                                                           H    H                114 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OSO.sub.3 H                                                                            O 5-propyl   7-Cl 4-OCH.sub.3                                                                           H    H                115 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-SCH.sub.3                                                                           H    H                116 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 SCH.sub.3                                                                       7-Cl 4-OCH.sub.3                                                                           H    H                117 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 SOCH.sub.3                                                                      7-Cl 4-OCH.sub.3                                                                           H    H                118 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 SO.sub.2 CH.sub.3                                                               7-Cl 4-OCH.sub.3                                                                           H    H                119 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 OCH.sub.3                                                                       7-Cl 4-OCH.sub.3                                                                           H    H                120 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OSO.sub.3 H                                                                            O CH.sub.2 SCH.sub.3                                                                       7-Cl 4-OCH.sub.3                                                                           H    H                121 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O CH.sub.2 SCH.sub.3                                                                       7-Cl 4-OCH.sub.3                                                                           H    H                122 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OPO.sub.3 H.sub.2                                                                      O CH.sub.2 SCH.sub.3                                                                       7-F  4-OCH.sub.3                                                                           H    H                123 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OPO.sub.3 H.sub.2                                                                      O CH.sub.2 SO.sub.2 CH.sub.3                                                               7-F  4-OCH.sub.3                                                                           H    H                132 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 SCH.sub.3                                                                       7-Pr 4-OCH.sub.3                                                                           H    H                133 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 SOCH.sub.3                                                                      7-Pr 4-OCH.sub.3                                                                           H    H                134 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 SO.sub.2 CH.sub.3                                                               7-Pr 4-OCH.sub.3                                                                           H    H                135 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O CH.sub.2 OCH.sub.3                                                                       7-Pr 4-OCH.sub.3                                                                           H    H                136 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OSO.sub.3 H                                                                            O CH.sub.2 SCH.sub.3                                                                       7-Pr 4-OCH.sub.3                                                                           H    H                137 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O CH.sub.2 SCH.sub.3                                                                       7-Pr 4-OCH.sub.3                                                                           H    H                138 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OPO.sub.3 H.sub.2                                                                      O CH.sub.2 SCH.sub.3                                                                       7-Pr 4-OCH.sub.3                                                                           H    H                139 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OPO.sub.3 H.sub.2                                                                      O CH.sub.2 SO.sub.2 CH.sub.3                                                               7-Pr 4-OCH.sub.3                                                                           H    H                140 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-CO.sub.2 H                                                                       4-OCH.sub.3                                                                           H    H                141 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-CO.sub.2 H                                                                          H    H                142 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-F  4-CO.sub.2 H                                                                          H    H                143 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-CH.sub.2 CHOHCH.sub. 2 OH                                                              7-Cl 4-CO.sub.2 H                                                                          H    H                144 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-CH.sub.2 CHOHCH.sub.2 OH                                                               7-F  4-CO.sub.2 H                                                                          H    H                145 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-CH.sub.2 CHOHCH.sub.3                                                                  7-Cl 4-CO.sub.2 H                                                                          H    H                146 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-CH.sub.2 CHOHCH.sub.3                                                                  7-F  4-CO.sub.2 H                                                                          H    H                147 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-SO.sub.3 H                                                                       4-OCH.sub.3                                                                           H    H                148 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-CH.sub.2 CH.sub.2 OH                                                                   7-Cl 4-CO.sub.2 H                                                                          H    H                149 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-C(CH.sub.3).sub.3                                                                      7-Cl 4-CO.sub.2 H                                                                          H    H                152 CH.sub.3                                                                            CH.sub.2 tetrazol                                                                      4-OH       O 5-propyl   7-Cl 4-CH.sub.3 O                                                                          H    H                153 CH.sub.3                                                                            CH.sub.2 tetrazol                                                                      4-OH       O 5-propyl   7-Cl 4-CH.sub.3 O                                                                          H    H                154 CH.sub.3                                                                            CH.sub.2 tetrazol                                                                      4-OH       O 5-propyl   H    4-CH.sub.3 O                                                                          H    H                157 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O H          H    H       H    H                158 CH.sub. 3                                                                           CH.sub.2 C.sub.6 H.sub.5                                                               4-OAc      O H          H    H       H    H                161 CH(CH.sub.3).sub.2                                                                  H        5-OH       O H          H    --      --   --               162 CH(CH.sub.3).sub.2                                                                  H        4-OH       O H          H    --      --   --               163 CH.sub.3                                                                            H        4-OH       O 5-propyl   7-Cl --      --   --               164 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O H          7-Cl 4-CH.sub.3 O                                                                          H    H                165 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-C.sub.4 H.sub.9                                                                        7-Cl 4-CH.sub.3 O                                                                          H    H                166 H     CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-CH.sub.3 O                                                                          H    H                167 Propyl                                                                              CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-CH.sub.3 O                                                                          H    H                168 CH.sub.3                                                                            CH.sub.3 CH--C.sub.6 H.sub.5                                                           4-OH       O 5-propyl   7-Cl 4-CH.sub.3 O                                                                          H    H                169 CH.sub.3                                                                            C.sub.7 H.sub.15                                                                       4-OH       O 5-propyl   H    --      --   --               170 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   6-OMe                                                                              4-CH.sub.3 O                                                                          H    H                171 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       S 5-propyl   7-Cl 4-CH.sub.3 O                                                                          H    H                172 CH.sub.3                                                                            C.sub.6 H.sub.5                                                                        4-OH       O 5-propyl   7-Cl H       H    H                173 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-Cl       7-Cl 4-CH.sub.3 O                                                                          H    H                174 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 4-Cl    H    H                175 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-propyl   7-Cl 2-CH.sub.3 O                                                                          4-CH.sub.3                                                                         H                178 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-Me       7-Cl 4-CH.sub.3 O                                                                          H    H                179 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-allyl    7-Cl 4-CH.sub.3 O                                                                          H    H                180 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-(CH.sub.2).sub.3 OH                                                                    7-Cl 4-CH.sub.3 O                                                                          H    H                181 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-(CH.sub.2).sub.2 CO.sub.2 H                                                            7-Cl 4-CH.sub.3 O                                                                          H    H                182 CH.sub.3                                                                            CH.sub.2 C.sub.6 H.sub.5                                                               4-OH       O 5-EtO      7-Cl 4-CH.sub.3 O                                                                          H    H                __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    More-Preferred Compounds of Formula I                                         R.sup.1                                                                              R.sup.2 R.sup.3    X Y       Y.sup.1                                                                           Y.sup.2 Y.sup.3                                                                            Y.sup.4                  __________________________________________________________________________    8  CH.sub.3                                                                          C.sub.2 H.sub.5                                                                       4-OH       O 5-allyl H   --      --   --                       14 CH.sub.3                                                                          CH.sub.2 -4-pyridyl                                                                   4-OH       O 5-propyl                                                                              H   H       H    H                        15 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OH       O 6-OH    H   H       H    H                        16 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-Propyl                                                                              H   4-OH    H    H                        17 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-Propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        33 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              H   4-Cl    H    H                        38 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        73 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           3-CHO                                                                              H                        74 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-Br    H    H                        75 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              H       H    H                        76 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OH       O 4-propyl                                                                              7-Cl                                                                              4-F     H    H                        77 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-Cl                                                                              4-OAc   H    H                        78 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              H   4-OH    H    H                        79 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OH       O 4-propyl                                                                              H   4-OH    H    H                        80 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OH       O H       H   4-OH    H    H                        81 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              7-OH       O H       H   4-OCH.sub.3                                                                           H    H                        82 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-Oallyl   O H       H   4-OCH.sub.3                                                                           H    H                        84 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        85 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        86 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCO.sub.2 CHClCH.sub.3                                                                 O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        87 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCO.sub.2 CH.sub.3                                                                     O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        88 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCO.sub.2 CH.sub.3                                                                     O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        89 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Br                                                                              4-OCH.sub.3                                                                           H    H                        90 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        91 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-allyl H   4-OCH.sub.3                                                                           H    H                        92 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O H       H   4-OCH.sub.3                                                                           H    H                        93 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 7-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        94 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-CH.sub.3                                                                        4-OCH.sub.3                                                                           H    H                        95 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Pr                                                                              4-OCH.sub.3                                                                           H    H                        96 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-Cl    7-Pr                                                                              4-OCH.sub.3                                                                           H    H                        97 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OPO.sub.3 H.sub.2                                                                      O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        98 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        99 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        100                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OAc      O 4-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        101                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OCO.sub.2 CH.sub.3                                                                     O 4-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        102                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OH       O 4-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        103                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.2 CO.sub.2 Et                                                               H    H                        104                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCH.sub.2 CO.sub.2 Et                                                                  O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.2 CO.sub.2                                                                  Ht   H                        105                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.2 CO.sub.2 H                                                                H    H                        109                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OH    H    H                        110                                                                              CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                     4-OAc      O H       H   4-OCH.sub.3                                                                           H    H                        111                                                                              CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                     4-OH       O H       H   4-OCH.sub.3                                                                           H    H                        112                                                                              CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                     4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        113                                                                              CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                     4-OH       O 5-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        114                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OSO.sub.3 H                                                                            O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        157                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O H       H   H       H    H                        165                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-C.sub.4 H.sub.9                                                                     7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        166                                                                              H   CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        167                                                                              Propyl                                                                            CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        168                                                                              CH.sub.3                                                                          CH.sub.3 CH--C.sub.6 H.sub.5                                                          4-OH       O 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        169                                                                              CH.sub.3                                                                          C.sub.7 H.sub.15                                                                      4-OH       O 5-propyl                                                                              H   --      --   --                       170                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              6-OMe                                                                             4-CH.sub.3 O                                                                          H    H                        171                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       S 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        172                                                                              CH.sub.3                                                                          C.sub.6 H.sub.5                                                                       4-OH       O 5-propyl                                                                              7-Cl                                                                              H       H    H                        174                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-Cl    H    H                        175                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              2-CH.sub.3 O                                                                          4-CH.sub.3 O                                                                       H                        178                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-Me    7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        179                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-allyl 7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        180                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-(CH.sub.2).sub.3 OH                                                                 7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        181                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-(CH.sub.2).sub.2 CO.sub.2 H                                                         7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        182                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-EtO   7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Most-Preferred Compounds of Formula I                                         R.sup.1                                                                              R.sup.2 R.sup.3    X Y       Y.sup.1                                                                           Y.sup.2 Y.sup.3                                                                            Y.sup.4                  __________________________________________________________________________    14 CH.sub.3                                                                          CH.sub.2 4-pyridyl                                                                    4-OH       O 5-propyl                                                                              H   H       H    H                        16 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              H   4-OH    H    H                        17 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        38 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        77 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-Cl                                                                              4-OAc   H    H                        78 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              H   4-OH    H    H                        84 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        85 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        86 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCO.sub.2 CHClCH.sub.3                                                                 O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        87 CH.sub.3                                                                          CH.sub. 2 C.sub.6 H.sub.5                                                             4-OCO.sub.2 CH.sub.3                                                                     O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        88 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCO.sub.2 CH.sub.3                                                                     O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        90 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        94 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-CH.sub.3                                                                        4-OCH.sub.3                                                                           H    H                        95 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Pr                                                                              4-OCH.sub.3                                                                           H    H                        97 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OPO.sub.3 H.sub.2                                                                      O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        98 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O 5-propyl                                                                              7-F 4-OCH.sub.3                                                                           H    H                        99 CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OCOCH.sub.2 CH.sub.2 CO.sub.2 H                                                        O 5-propyl                                                                              7-Cl                                                                              4-OH.sub.3                                                                            H    H                        100                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OAc      O 4-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        101                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OCO.sub.2 CH.sub.3                                                                     O 4-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        102                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              5-OH       O 4-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        103                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OAc      O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.2 CO.sub.2 Et                                                               H    H                        105                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.2 CO.sub.2 H                                                                H    H                        109                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OH    H    H                        112                                                                              CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                     4-OH       O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        113                                                                              CH.sub.3                                                                          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                     4-OH       O 5-propyl                                                                              H   4-OCH.sub.3                                                                           H    H                        114                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OSO.sub.3 H                                                                            O 5-propyl                                                                              7-Cl                                                                              4-OCH.sub.3                                                                           H    H                        157                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O H       H   H       H    H                        165                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-C.sub.4 H.sub.9                                                                     7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        166                                                                              H   CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        167                                                                              Propyl                                                                            CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        168                                                                              CH.sub.3                                                                          CH.sub.3 CH--C.sub.6 H.sub.5                                                          4-OH       O 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        169                                                                              CH.sub.3                                                                          C.sub.7 H.sub.15                                                                      4-OH       O 5-propyl                                                                              H   --      --   --                       171                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       S 5-propyl                                                                              7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        172                                                                              CH.sub.3                                                                          C.sub.6 H.sub.5                                                                       4-OH       O 5-propyl                                                                              7-Cl                                                                              H       H    H                        174                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              4-Cl    H    H                        175                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-propyl                                                                              7-Cl                                                                              2-CH.sub.3 O                                                                          4-CH.sub.3 O                                                                       H                        178                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-Me    7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        179                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-allyl 7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        180                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-(CH.sub.2).sub.3 OH                                                                 7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        181                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-(CH.sub.2).sub.2 CO.sub.2 H                                                         7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        182                                                                              CH.sub.3                                                                          CH.sub.2 C.sub.6 H.sub.5                                                              4-OH       O 5-EtO   7-Cl                                                                              4-CH.sub.3 O                                                                          H    H                        __________________________________________________________________________

The following reaction schemes illustrate the preparation of compoundsof the present invention: ##STR11##

A suitable acetophenone (II) wherein Y is as defined above is reactedwith a substituted phenacyl bromide (III) wherein Y is as defined aboveat a temperature ranging from room temperature to about 150° C. in aninert solvent (preferably at reflux in acetone) in the presence of abase (for example, an alkali metal hydroxide or carbonate) to give thecorresponding benzoyl benzofuran derivative (IV). The compound of theformula IV is then reduced to give the compound of Formula I. Forexample, subsequent treatment of IV with hydrazine and a strong base ata temperature of about 150° to 210° C. preferably using the Huang Minlonmodification of Wolff Kishner conditions (J. Am. Chem. Soc. 68, 2487(1946)) yields the desired benzyl benzofuran derivative I.Alternatively, compound IV can be reduced to compound I using the zincamalgam and a strong acid (preferably hydrochloric acid). See, forexample, Ber. 46, 1837 (1913). Alternatively, compound IV can be reducedto compound I using a mixture of lithium aluminum hydride and aluminumchloride in ether or tetrahydrofuran as solvent at a temperature rangevarying from 0° C. to 65° C. ##STR12##

According to the method of Scheme II, hydrolysis of an appropriatecompound of the formula VI, wherein Y is as defined above, with a strongacid and/or a strong base in water, or a mixture of water and a watersoluble solvent, at a temperature ranging from room temperature toreflux (preferably, reflux) yeilds the corresponding acid of formulaVII. Compounds of the formula VI are disclosed in U.S. Ser. No. 661,645,filed Oct. 17, 1984 , the disclosure of which is hereby incorporatedherein by reference. The acid of formula VII is then decarboxylated toyield the corresponding benzofuran derivative of the formula VIII. Thismay be done by heating the acid in quinoline in the presence of copper.It can also be done by heating at reflux compound VII with a strong acidsuch as hydrochloric acid in a two-phase system made up of toluene andagueous acid. Benzene or xylene or other aromatic hydrocarbons can besubstituted for toluene. ##STR13## wherein R⁶ is C₁ to C₅ alkyl,(CH₂)_(n-1) Het, or --(CH₂)_(n-1) -PhY₂ Y₃ Y₄

Following Scheme III, Compound VIII, which is unsubstituted in position2,can be reacted with an acid halide IX in the presence of a Lewis acid.Preferably aluminum chloride, to yield the 2-acyl derivative X. Thisreaction is best carried out in a solvent such as methylene chloride orethylene dichloride at a temperature ranging from 0° to 25° C. Thecompound of the Formula X is then reduced to give the compound ofFormula I. For example, subseguent treatment of X with hydrazine and astrong base at a temperature of about 150° to 210° C. using theHuang-Minlon modification of Wolff-Kishner conditions (J. Am. Chem. Soc.68, 2487 (1946)) yields the desired alkyl benzofuran derivative I.Alternatively, compound X can be reduced to compound I using the zincamalgam and a strong acid (preferably hydrochloric acid). See, forexample, Bev., 46, 1837 (1913).

Alternatively, compound X can be reduced to compound I using a mixtureof lithium aluminum hydride and aluminum chloride in ether ortetrahydrofuran as solvent at a temperature range varying from 0° to 65°C. ##STR14##

Scheme IV describes another synthesis of compounds of Formula I. Acarboxylic acid derivative VII is reacted with dichloromethyl methylether at reflux for 30 minutes to 2 hours to yield the correspondingacid chloride XI. This acid choride XI can then be reacted with asuitably substituted aromatic derivative such as anisole, toluene, orthe like to yield the desired 2 benzoyl derivative IV. TheFriedel-Crafts aroylation reaction is best carried out in an inertsolvent such as methylene chloride or ethylene dichloride and iscatalyzed very efficiently by a Lewis acid, preferably aluminumchloride. The 2-benzoyl derivative IV is then reduced to the 2-benzylderivative V. For example, subsequent treatment of IV with hydrazine anda strong base at a temperature of about 150° to 210° C. preferably usingthe Huang Minlon modification of Wolff-Kishner conditions (J. Am. Chem.Soc. 68, 2487 (1946)) yields the desired benzyl benzofuran derivative V.Alternatively, compound IV can be reduced to compound V using the zincamalgam and a strong acid (preferably hydrochloric acid). See, forexample, Ber. 46, 1837 (1913). Alternatively, compound IV can be reducedto compound V using a mixture of lithium aluminum hydride and aluminumchloride in ether or tetrahydrofuran as solvent at a temperature rangevarying from 0° C. to 65° C.

In those instances when asymmetric centers are present, more than onestereoisomer is possible, and all possible isomeric forms are deemed tobe included within the planar structural representations shown.Optically active (R) and (S) isomers may be resolved using conventionaltechniques known to the skilled artisan.

The compounds of Formula I may be tested using one or more of thefollowing assays to determine their mammalian leukotriene biosynthesisinhibiting activity and other relevant activities.

RBL 1 5 Lipoxygenase

Rat basophilic leukemia (RBL-1) cells are sonicated and centrifuged at125000 ×g. The resulting supernatant fraction is incubated witharachidonic acid (labelled with ¹⁴ C) to convert a portion of it to ¹⁴C-5(S) hydroxyicosatetraenoic acid (5-HETE). Compounds being evaluatedas inhibitors of 5-Lipoxygenase are added prior to the addition ofarachidonic acid. 5-HETE is isolated by extraction and paperchromatogrphy, and quantitated by determining the amount ofradioactivity (cpm) associated with 5-HETE.

Reference: Egan, R. W.; Tischler, A. M.; Baptista, E. H.; Ham, E. A.;Soderman, D. D.; and Gale, P. H.; Advances in Prostaglandin, Thromboxaneand Leukotriene Research, 11, 151,(1983), (Samuelsson, B.; Ramwell, P.W.; and Paoletti, R.; (eds.), Raven Press, N.Y.

Mouse Macrophase Assay

Mouse peritoneal macrophages are treated sequentially with arachidonicacid (labelled with tritium); the compound being evaluated as aninhibitor, and a stimulator (zymosan). Metabolites derived fromarachidonic acid (PGE₂, 6-keto PG-F_(1a) and leukotriene C₄) areseparated from the incubation medium by extraction and chromatography,and then quantitated by determining the amount of radioactivity (cpm)associated with each of them. Inhibitors cause a reduction in the amountof radioactivity (cpm) associated with a given metabolite. (Thisprotocol is identical to that described in the reference except that theradioactivity herein associated with the LTC₄ is determined by countingan aliquot of the final aqueous solution directly rather thanchromatographing it first.)

Reference: Humes, J. L. et al., J. Biol. Chem., 257, 1591-4,(1982).

Rat Polymorphonuclear Leukocyte (P.M.N.) Assay

Rats under ether anesthesia are injected (intraperitoneally) with 8 mlof a suspension of sodium caseinate (6 grams in about 50 ml water).After 15 to 24 hours the rats are sacrificed (CO₂) and the cells fromthe peritoneal cavity are recovered by lavage with 20 ml of buffer(Eagles Minimal Essential Medium containing 30 mM HERPES adjusted to pH7.4 with NaOH). The cells are pelleted (350 ×g, 5 min.), resuspended inbuffer with vigorous shaking, filtered through lens paper, recentrifugedand finally suspended in buffer at a concentration of 10 cells/ml. A 500μl aliquot of the suspension (PMN) and test compound are preincubatedfor 2 minutes at 37° C., followed by the addition of 10 μM A 23187calcium ionophore (Calbiochem). The suspension is stirred for anadditional 4 minutes then bioassayed for LTB₄ content by adding analiquot to a second 500 μl portion of the PMN at 37° C. The LTB₄produced in the first incubation causes aggregation of the second PMN,is measured as a change in light transmission. The size of the assayaliquot is chosen to give a submaximal transmission change (usually-70%) for the untreated control. The percentage inhibition of LTB₄formation is calculated from the ratio of transmission change in thesample to the transmission change in the compound-free control.

Antigen Challenge `in vitro` Assay

Male guinea pigs weighing 300-350 g are sensitized by injecting(intraperitoneally) 0.5 ml of a suspension containing 0.4 mg of eggalbumin (Ovalbumin, Grade V, Sigma Chemical Co.) and 4.0 g aluminumhydroxide in 19.6 ml of saline. Two weeks are permitted forsensitization to occur.

Three sensitized guinea pigs are stunned and exanguinated. The tracheasare removed, freed of adhering tissue and divided longitudinally bycutting through the cartilaginous tissue directly opposite the muscleinsertion. Each opened trachea is then transected between every secondcartilage. Four of the cut sections are tied together, end to end, in aseries with No.7 silk thread ensuring that the tracheal muscles are allin the same vertical plane. Thus, each chain consists of tissue fromthree different animals.

The chain so formed is then suspended under 1 g of tension (by silk tiesat each end) in a 20 ml organ bath containing 10 ml of modified¹Krebs-Henseleit buffer solution gassed with 95% O₂ and 5% CO₂ at 37° C.Mepyramine (0.55 μg/ml) and indomethacin (2.67 μg/ml) are added to thebuffer to avoid the contribution of histamine receptors andcyclooxygenase products to the contraction. To record responses one endof the tracheal chain is attached to a Gould-Statham UC-2 forcedisplacement transducer which is connected to a Beckman TypeR-dynograph. The preparations are allowed to equilibrate for one hourduring which time the tissues are automatically washed (10 ml volumedisplacement) every 6 minutes.

After the equilibration period the tissues are primed with methacholine(3 μg/ml; 1.5×10⁻⁵ M), washed and allowed to recover to baseline. Thetissues are treated again with a second dose of methacholine, washed,allowed to return to baseline and washed for an additional hour.

Two chains are used as a control. These are incubated in a concentrationof egg albumin sufficient to induce an average contraction of 50-80% ofthe methacholine response.

Each compound to be tested is added to two their baths (at a finalconcentration in each bath of 10 μg/ml) 15 minutes prior to challengingthe fresh chains with egg albumin.

The response of the challenged tissue is expressed as a percentage ofthe methacholine maximum. The percentage inhibition for each compound isthen calculated. Compounds which at 10 μg/ml (final concentration)inhibit the egg albumin response by 50% or more are retested at a lowerconcentration.

Asthmatic Rat Assay

Rats are obtained from an inbred line of asthmatic rats. Both female andmale rats from 200 to 300 g are used.

Egg albumin (EA), grade V, crystallized and lyophilized, is obtainedfrom Sigma Chemical Co., St. Louis. Bordetella pertussis vaccine,containing 30×10⁹ killed bacteria per ml is obtained from the InstituteArmand-Frappier, Laval des Rapides, Quebec. Aluminum hydroxide isobtained from the Regis Chemical Company, Chicago.

The challenge and subseguent respiratory recordings are carried out in aclear plastic box with internal dimensions 10×6×4 inches. The top of thebox is removable; in use, it is held firmly in place by four clamps andan airtight seal is maintained by a soft rubber gasket. Through thecenter of each end of the chamber a Devilbiss nebulizer (No. 40) isinserted via an airtight seal and each end of the box also has anoutlet. A Fleisch No. 0000 pneumotachograph is inserted into one end ofthe box and coupled to a Grass volumetric pressure transducer (PT5-A)which is then connected to a Beckman Type R Dynograph throughappropriate couplers. While aerosolizing the antigen, the outlets areopen and the pneumotachograph is isolated from the chamber. The outletsare closed and the pneumotachograph and the chamber are connected duringthe recording of the respiratory patterns. For challenge, 2 ml of a 3%solution of antigen in saline is placed into each nebulizer and theaerosol is generated with air from a small Potter diaphragm pumpoperating at 10 psi and a flow of 8 liters/minute.

Rats are sensitized by injecting (subcutaneously) 1 ml of a suspensioncontaining 1 mg EA and 200 mg aluminum hydroxide in saline.Simultaneously, they receive an injection (intra peritoneally) of 0.5 mlof B. pertussis vaccine. They are used between days 14 and 18postsensitization. In order to eliminate the serotonin component of theresponse, rats are pretreated intravenously 5 minutes prior to aerosolchallenge with 30 gm/kg methylserzide. Rats are then exposed to anaerosol of 3% EA in saline for exactly 1 minute, then their respiratoryprofiles are recorded for a further 25 to 30 minutes. The duration ofcontinuous dyspnoea is measured from the respiratory recordings.

Compounds are generally administered either intraperitoneally 1 hourprior to challenge or orally 1 and 1/2 hours prior to challenge. Theyare either dissolved in dimethylsulfoxide or suspended in 0.1% methoceland 0.5% Tween 80. The volume injected is 2 ml/kg (intraperitoneally) or10 ml/kg (orally). Prior to oral treatment rats are starved overnight.Their activity is determined in terms of their ability to decrease theduration of symptoms of dyspnoea in comparison with a group ofvehicle-treated controls. Usually, a compound is evaluated at a seriesof doses and an ED₅₀ is determined. This is defined as the dose (mg/kg)which would inhibit the duration of symptoms by 50%.

PAF-Induced Hyperalgesia Assay

Female Sprague-Dawley rats, 35 to 40 g are fasted overnight. Plateletactivating factor, PAF, (L-lecithin B-acetyl O-alkyl) 1 μg/0.1 ml isgiven by subplantar injection in the rat paw. The compounds to beevaluated are homogenized in Aqueous Vehicle (0.9% benzyl alcohol, 0.5%Tween 80 and 0.4% methylcellulose) and administered orally in a volumeof 0.1 ml, 30 minutes prior to PAF.

Animals are tested 1, 2, 3 and 4 hours after PAF administration. Thevocalization threshold, defined as the pressure (mmHg) needed to evoke asqueak response, was recorded for both the injected and contralateralpaw. No animal is subjected to pressure greater than 60 mmHg.Hyperalgesia is defined as a decrease in vocalization threshold ascompared to a normal paw. Percent inhibition of hyperalgesia iscalculated as the proportion of animals with vocalization thresholdsgreater than 200% of controls.

Brewer's Yeast Hyperalgesia Assay

The standard method [Winter, C. A. et al., J. Pharm. Exp. Ther. 150,165-171 (1965)] for yeast hyperalgesia is used. Female Spraque-Dawleyrates, 35-40 g are fasted overnight. A 5% solution (volume 0.1 ml) ofBrewer's yeast is injected into the rat paw. The compound is homogenizedin aqueous vehicle and given orally 2 hours after yeast. Vocalizationthresholds are recorded 1 hour after drug (3 hours after yeast). Percentinhibition of hyperalgesia is determined by the proportion of animalswith vocalization thresholds greater than 25 mmHg.

The compounds of the Formula I have unexpected activity as inhibitors ofthe mammalian biosynthesis of leukotriene B₄, as well as leukotrienesC₄, D₄, E₄ and F₄, the active elements of the slow reacting substance ofanaphylaxis (SRS-A). The compounds of Formula I act as inhibitors of themammalian 5-lipoxygenase enzyme system of the arachidonic acid cascade.This inhibition of the mammalian biosynthesis of leukotrienes indicatesthat the compositions are useful to treat, prevent or ameliorate, inmammals and especially in humans (1) pulmonary conditions includingdiseases such as asthma, (2) allergies and allergic reactions such asallergic rhinitis, contact dermatitis, allergic conjunctivitis and thelike, (3) inflammation such as arthritis, (4) pain, (5) skin conditionssuch as psoriasis and the like, and (6) cardiovascular conditions suchas angina and the like, and that the compounds are cytoprotectiveagents.

Thus, the compounds of the present invention may also be used to treator prevent mammalian (especially, human) disease states such as erosivegastritis; erosive esophagitis; inflammatory bowel disease; ethanolinduced hemorrhagic erosions; hepatic ischemia; noxious agent induceddamage or necrosis of hepatic, pancreatic, renal, or myocardial tissue,liver parenchymal damage caused by hepatoxic agents such as CCl₄ and Dgalactosamine; ischemic renal failure; disease-induced hepatic damage,bile salt induced pancreatic or gastric damage; trauma- orstress-induced cell damage; and glycerol-induced renal failure.

The cytoprotective activity of a compound may be observed in both animaland man by noting the increased resistance of the gastrointestinalmucosa to the noxious effects of strong irritants, for example, theulcerogenic effects of aspirin or indomethacin. In addition to lesseningthe effect of non-steroidal anti-inflammatory drugs on thegastrointestinal tract, animal studies show that cytoprotectivecompounds will prevent gastric lesions induced by oral administration ofstrong acids, strong bases, ethanol, hypertonic saline solutions and thelike.

Two assays can be used to measure cytoprotective ability. These assaysare; (A) an ethanol-induced lesion assay and (B) an indomethacin-inducedulcer assay.

A. Ethanol-Induced Gastric Ulcer Assay

Twenty-four hour fasted Sprague-Dawley (S.D.) rats are perorally (p.o.)does with 1.0 ml absolute ethanol. Fifteen to thirty minutes prior toethanol administration, groups of rats each receive either an agueousvehicle (aqueous methylcellulose 5% wt.) or the test compound at variousdoses perorally. One hour later, the animals are sacrificed and stomachmucosa are examined for resulting lesions.

B. Indomethacin-Induced Ulcer Assay

Indomethacin, 10 mg/kg p.o., is used to induce ulcers in 24 hour fastedS. K. rats. Fifteen minutes prior to indomethacin administration, groupsof rats each receive either an aqueous vehicle (5% by weightmethylcellulose) or the test compound at various doses perorally. Fourhours later the animals are sacrifices and stomach mucosa are examinedfor resulting ulcers.

The magnitude of a prophylactic or therapeutic dose of a compound offormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of formula Iand its route of administration. When a compound of formula I is used ina pharmaceutical composition, the effective concentration in thecomposition will vary as required by the mode of administration, dosageform and pharmocological effect and level desired. In general, the dailydose range for anti-asthmatic, anti-allergic or anti inflammatory useand, generally, uses other than cytoprotection lies within the range offrom about 0.01 mg to about 100 mg per kg body weight of a mammal. Thisdosage may be administered in a single or divided individual doses. Moreor less of the general daily dosage may be necessary depending upon theindividual needs of the patient.

The exact amount of a compound of the Formula I to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells or to avoid future damage, on the nature ofthe damaged cells (e.g., gastro intestinal ulcerations vs. nephroticnecrosis), and on the nature of the causative agent. An example of theuse of a compound of the Formula I in avoiding future damage would beco-administration of a compound of the Formula I with a non-steroidalanti-inflammatory drug that might otherwise cause such damage (forexample, indomethacin). For such use, the compound of Formula I isadministered from 30 minutes prior up to 30 minutes after administrationof the NSAID (for example, in a combination dosage form). Preferablyitis administered prior to or simultaneous with the NSAID.

The effective daily dosage level for compounds of Formulae I inducingcytoprotection in mammals, especially humans, will generally range fromabout 0.002 mg/kg to about 100 mg/kg, preferably from about 0.02 mg/kgto about 30 mg/kg. The dosage may be administered in single or divideddoses.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dosage of a leukotrieneantagonist. For example, oral, rectal, transdermal parenteral,intramuscular, intravenous and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsulesand the like.

For treating pulmonary conditions such as asthma, the mode ofadministration may be oral, parenteral, by inhalation, by suppositoryand the like. Suitable oral dosage forms are tablets, elixirs,emulsions, solutions, capsules, including delayed or sustained releasecapsules and the like. Parenteral dosage forms include solutions,emulsions and the like. Dosage forms for administration by inhalationincluding sprays, aerosols and the like. These inhalation formulationsmay be administered in metered doses ranging from about 0.1 μg to about200 μg, administered as needed.

For treating allergies or allergic reactions, such as allergicconjunctivitis, allergic rhinitis and the like, the Formula I compoundmay be administered by any conventional mode, e.g., orally,parenterally, topically, subcutaneously, by inhalation and the like. Theoral and parenteral dosage forms are the same type as for the pulmonarytreatment. The topical application dosage forms include ointments,salves, controlled release patches, emulsions, solutions, thixotropicformulations, powders, sprays and the like. For topical application, thepercent by weight active ingredient (Formula I compound) may vary fromabout 001 to about 10%.

For treating inflammation the mode of administration may be oral,parenteral, by suppository and the like. The various dosage forms arethe same as those described above.

For treating skin diseases such as psoriasis, atopic dermatitis and thelike, oral, topical or parenteral administration is useful. For topicalapplication to the diseased area salves, patches, controlled releasepatches, emulsions, etc., are convenient dosage forms.

For use as an analgesic, i.e., for treating pain, any suitable mode ofadministration may be used, e.g., oral, parenteral, by insufflation, bysuppository and the like.

Fo treating cardiovascular conditions such as angina pectoris, etc., anysuitable mode of administration, e.g. oral, parenteral, topical,insufflation, etc. and dosage form e.g. pills, liguid formulations,controlled release capsules, controlled release skin patches, etc. maybe used.

The pharmaceutical compositions of the present invention comprise acompound of formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include sodium,potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper,manganous, aluminum, ferric, manganic salts and the like. Particularlypreferred are the ammonium, potassium, sodium, calcium and magnesiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethlenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. For a usefuldiscussion of pharmaceutical salts see S. M. Berge et al., Journal ofPharmaceutical Sciences, 66, 119 (1977), the disclosure of which ishereby incorporated herein by reference.

The compositions include compositions suitable for oral, rectal,ophthalmic, pummonary, nasal, dermal, topical or parenteral (includingsubcutaneous, intramuscular and intravenous) administration, althoughthe most suitable route in any given case will depend on the nature anseverity of the conditions being treated and on the nature of the activeingredient. They may be conveniently presented in unit dosage form andprepared by any of the methods well known in the art of pharmacy.

For use where a composition for intravenous administration is employed,a suitable dosage range for anti-asthmatic, anti-inflammatory oranti-allergic use and, generally, uses other than cytoprotection is fromabout 0.01 mg to about 20 mg (preferably from about 0.1 mg to about 10mg) of a compound of Formula I per kg of body weight per day and forcytoprotective use from about 0.002 mg to about 100 mg (preferably fromabout 0.02 mg to about 30 mg and more preferably from about 0.1 mg toabout 10 mg) of a compound of Formula I of body weight per day. In thecase where an oral composition is employed, a suitable dosage range foranti-asthmatic, anti-inflammatory or anti-allergic use and, generally,uses other than cytoprotection is from about 1 to about 100 of acompound of Formula I per kg of body weight per day, preferably fromabout 5 mg to about 40 mg per kg and for cytoprot-ective use from about0.01 mg to about 100 mg (preferably from about 0.1 mg to about 30 mg andmore preferably from about 0.1 mg to about 10 mg) of a compound ofFormula I per kg of body weight per day.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or a nebuliser. The preferred composition forminhalation is a powder which may be formulated as a cartridge from whichthe powder composition may be inhaled with the aid of a suitable device.In the case of a pressurized aerosol, the dosage unit may be determinedby providing a valve to deliver a metered amount.

In practical use, leukotriene antagonists of Formula I can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniguesand using conventional ingredients, e.g. diluents, carriers, etc. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired form administration, e.g., oral or intravenous. Inpreparing the compositions for oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, waterglycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like in the case of oral liguid preparations, such as,for example, suspensions, elixirs and solutions; or carriers such asstarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like in the case of oral solidpreparations such as, for example, powders, capsules and tablets andcapsules represent the most advantageous oral dosage unit form, in whichcase solid pharmaceutical carriers are obviousy employed. If desired,tablets may be sugar coated or enteric coated by standard technigues.

In addition to the common dosage forms set above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719, thedisclosures of which are incorporated herein by reference.

Dosage forms for application to treat the eye are disclosed in U.S. Pat.No. 4,348,398, the disclosure of which is incorporated herein byreference.

Pharmaceutical compositions of the present invention suitable for oraladministration and by inhalation in the case of asthma therapy may bepresented as discrete units such as capsules, cachets or tablets eachcontaining an predetermined amount of the active ingredient, as a powderor granules or as a solution or suspension in an agueous liguid, a nonagueous liguid, an oil in-water emulsion or a water in-oil liguidemulsion. Such compositions may be prepared by any of the methods ofpharmacy but all methods include the step of bringing into associationthe active ingredient with the carrier which constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liguidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product into the desired presentation. Forexample, a tablet may be prepared by compression or molding, optionallywith one or more accessory ingredients. Compressed tablets may beprepared by compressing in a suitable machine, the active ingredient ina free flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliguid diluent. Desirably, each tablet contains from about 25 mg toabout 500 mg of the active ingredient and each cachet or capsulecontains from about 25 to about 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosageforms:

    ______________________________________                                        Injectible Suspension                                                                            mg/mL                                                      ______________________________________                                        Compound of Formula I                                                                            2                                                          Methylcellulose    5.0                                                        Tween 80           0.5                                                        Benzyl alcohol     9.0                                                        Methyl paraben     1.8                                                        Propyl paraben     0.2                                                        Water for injection to a total volume of 1 ml                                 ______________________________________                                        Aerosol for Oral Inhibition                                                                      mg/can (200 doses/can)                                     ______________________________________                                        Compound of Formula I                                                                            2-40                                                       Oleic Acid         0.2-4.0                                                    Trichloromonofluoro methane                                                                      5,000-8,000*                                               Dichloromonofluoro methane                                                                       15,000-12,400*                                             ______________________________________                                        Cream              mg/g                                                       ______________________________________                                        Compound of Formula I                                                                            1-100                                                      Cetyl alcohol      130.0                                                      Sodium Lauryl Sulfate                                                                            15.0                                                       Propylene Glycol   100.0                                                      Methyl paraben     1.8                                                        Propyl paraben     1.2                                                        Purified Water of sufficient quantity to make total 1 g                       ______________________________________                                        Ointment           mg/g                                                       ______________________________________                                        Compound of Formula I                                                                            1-100                                                      Methyl paraben     1.8                                                        Propyl paraben     1.2                                                        Petrolatum of sufficient quantity to make total 1 g                           ______________________________________                                        Tablet             mg/tablet                                                  ______________________________________                                        Compound of Formula I                                                                            25                                                         Microcrystalline Cellulose                                                                       325                                                        Providone          14.0                                                       Microcrystalline Cellulose                                                                       90.0                                                       Pregelatinized Starch                                                                            43.5                                                       Magnesium Stearate 2.5                                                                           500                                                        ______________________________________                                        Capsule            mg/capsule                                                 ______________________________________                                        Compound of Formula I                                                                            25                                                         Lactose Powder     573.5                                                      Magnesium Stearate 1.5                                                                           600                                                        ______________________________________                                         *To a total volume of 1 ml                                               

In addition to the compounds of Formula I, the pharmaceuticalcompositions of the present invention can also contain other activeingredients, such as cyclooxygenase inhibitors, non steroidalanti-inflammatory drugs (NSAIDs), peripheral analgesic agents such aszomepirac diflunisal and the like. The weight ratio of the compound ofthe Formula I to the second active ingredient may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the Formula I is combined with an NSAID the weight ratio of thecompound of the Formula I to the NSAID will generally range from about1000:1 to about 1:1000, preferably about 200:1 to about 1:200.Combinations of a compound of the Formula I and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: ibuprofen,ibuprufen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen,flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen,carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen,alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid.Structurally related propionic acid derivatives having similar analgesicand anti-inflammatory properties are also intended to be included inthis group.

Thus, "propionic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a freeCH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in the formof a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO Na⁻ ⁺ or--CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via a carbonylfunction to a ring system, preferably to an aromatic ring system.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozicacid. Structually related acetic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free --CH₂COOH group (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid.Structurally related fenamic acid derivatives having similar analgesicand anti-inflammatory properties are also intended to be encompassed bythis group.

Thus, "fenamic acid derivatives" as defined herein are non narcoticanalgesics/non-steroidal anti inflammatory drugs which contain the basicstructure: ##STR15## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and anti-inflammatory propertiesare also intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenon-narcotic analgesics/non-steroidal anti-inflammatory drugs whichcontain the basic structure: ##STR16## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO⁻ Na⁺.

The oxicams which can be used in the present invention comprise:piroxicam, sudoxicam, isoxicam and 4 hydroxyl-1,2-benzothiazine1,1-dioxide 4-(N-phenyl)-carboxamide. Structurally related oxicamshaving similar analgesic and anti-inflammatory properties are alsointended to be encompassed by this group.

Thus, "oxicams" as defined herein are non-narcotic analgesics/nonsteroidal anti-inflammatory drugs which have the general formula:##STR17## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: acemetacin, alminoprofen, amfenacsodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazaclysinate, benzydanine, beprozin, broperamole, bufezolac, carprofen,cinmetacin, ciproguazone, clidanac, cloximate, dazidamine, deboxamet,delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine,difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole,etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac,fenclorac, fendosal, fenflumizole, fentiazac, feprazone, floctafenine,flunixin, flunoxaprofen, fluproguazone, fopirtoline, fosfosal,furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac,isonixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide,lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysinclonixinate, meclofenamate sodium, meseclazone, miroprofen, nabumetone,nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin,perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, pirprofen, pranoprofen, proglumetacin maleate, proguazone,pyridoxiprofen, sudoxicam, suprofen, talmetacin, talniflumate,tenoxicam, thiazolinobutazone, thielavin B, tiaprofenic acid, tiaramideHCl, tiflamizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol,tryptamid, ufenamate, and zidometacin.

The following NSAIDs, designated by company code number, may also beused: 480156S, AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001,BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182,KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ON03144, PR823, PV102,PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281,SY6001, TA60, TVX2706, U60257, UR2301 and WY41770.

Finally, NSAIDs which may also be used include the salicylates,specifically aspirin, and the phenylbutazones, and pharmaceuticallyacceptable salts thereof.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain inhibitors of the biosynthesis of the leukotrienes such as aredisclosed in U.S.Pat. Nos. 4,666,907, 4,663,307, 4,611,056, and4,634,766, which are hereby incorporated herein by reference.

The compounds of the Formula I may also be used in combination withleukotriene antagonists such as those disclosed in EP 106,565 (April 25,1984) and EP 104,885 (April 4, 1984) which are hereby incorporatedherein by reference and others known in the art such as those disclosedin European Patent Application Nos. 56,172 and 61,800; and in U.K.Patent Specification No. 2,058,785, which are hereby incorporated hereinby reference.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain as the second active ingredient, antihistaminic agents such asbenadryl, dramamine, histadyl, phenergan and the like. Alternatively,they may include prostaglandin antagonists such as those disclosed inU.S. Pat. No. 4,536,507 or thromboxane antagonists such as thosedisclosed in U.S. Pat. No. 4,237,160. They may also contain histidindecarboxyase inhibitors such as α-fluoromethylhistidine, described inU.S. Pat. No. 4,325,961. The compounds of the Formula I may also beadvantageously combined with an H₁ or H₂ -receptor antagonist, such asfor instance cimetidine, ranitidine, terfenadine, famotidine,aminothiadiazoles disclosed in EP 40,696 (December 2, 1981) and likecompounds, such as those disclosed in U.S. Pat. Nos. 4,283,408;4,362,736; and 4,394,508. The pharmaceutical compositions may alsocontain a K+/H+ ATPase inhibitor such as omeprazole, disclosed in U.S.Pat. No. 4,255,431, and the like. Each of the references referred to inthis paragraph is hereby incorporated herein by reference.

The following examples illustrate the present invention without,however, limiting the same thereto. All temperatures are in degreesCelsius.

EXAMPLE 1 4 hydroxy-2 (4-methoxybenzyl)-3-methyl-5-benzofuran Step APreparation of4-hydroxy-2-(4-methoxybenzoyl)-3-methyl-5-propylbenzofuran

A mixture of 2,6-dihydroxy-5-propyl acetophenone (5.8 g; 30 mmoles),ω-bromo-p-methoxyacetophenone (6.8 g; 30 mmoles), anhydrous potassiumcarbonate (4.1 g; 30 mmoles) and acetone (150 ml) was refluxed for 22hours. The mixture was filtered and concentrated. The residue wasdissolved in dichloromethane (500 ml) and extracted with 1 N sodiumhydroxide (2×200 ml) and water (200 ml). The dichloromethane solutioncontaining the product was dried (Na₂ SO₄), filtered, concentrated, andchromatographed to obtain 7.2 g of the title compound as a solid. Asample was recrystallized from 10% ethyl acetate in hexane.

m.p. 114°-116° C.

Calcd for C₂₀ H₂₀ O₄ : C, 74.05; H, 6.21. Found: C, 74.30; H, 6.18.

Step B Preparation of4-hydroxy-2-(4-methoxybenzyl)-3-methyl-5-propylbenzofuran (7.2 g; 22mmoles), potassium hydroxide pellets (8.7 g; 155 mmoles), ethyleneglycol (100 ml) and 99% hydrazine (3.0 ml) was heated with stirring andmaintaining the internal temperature between 130° C. and 150° C. for 4hours. The internal temperature was permitted to rise to 175° C. for 1hour and excess water was always allowed to escape. The mixture wascooled and poured into excess 20% citric acid solution. The mixture wasextracted with ether, washed with water, dried (Na₂ SO₄), filtered,concentrated, and chromatographed to give 4 grams of the title compound.

m.p. 83°-86° C.

Calcd for C₂₀ H₂₂ O₃ : C, 77.39; H, 7.14. Found: C, 77.39; H, 7.06.

EXAMPLE 2 4-hydroxy-2-(4-hydroxybenzyl)-3-methyl-5-propylbenzofuran

Under nitrogen atmosphere, ethanethiol (4.9 g; 80 mmoles) was addeddropwise over 5 minutes to a mixture Of 99% sodium hydride (1.9 g; 80mmoles) in dimethylformamide (100 ml). After stirring for 15 minutes, asolution of 4-hydroxy-2-(4-methoxybenzyl)-3-methyl-5-propylbenzofuran(2.4 g; 8mmoles) in dimethylformamide (5 ml) was added in one portion.The mixture was refluxed for 2 hours, cooled, acidified with 20% citricacid solution and extracted with ether. The ether solution was washedwith water, dried (Na₂ SO₄), filtered, concentrated, and chromatographedto obtain 2.2 g of the title compound as an oil which crystallized froman ether hexane mixture.

m.p. 117°-120° C.

Calcd for C₁₉ H₂₀ O₃ : C, 77.00; H, 6.80. Found: C, 76.66; H, 7.32.

EXAMPLE 3 4-hydroxy-3-methyl-5-propyl-2-(4-pyridylmethyl)-benzofuranStep A Preparation of 4-hydroxy-3-methyl 5-propyl-2 -(isonicotinoyl)benzofuran

A mixture of 2,6-dihydroxy-5-propylaceto-phenone (5.8 g; 30mmoles),4-bromoacetylpyridine hydrobromide (16.8 g; 60mmoles), anhydrouspotassium carbonate (16.5 g; 120mmoles) and acetone (200 ml) wasrefluxed for 22 hours. The mixture was filtered, concentrated, andchromatographed to obtain 2 g of the title compound.

m.p. 203°-205° C.

Calcd for C₁₈ H₁₇ NO₃ : C, 73.20; H, 5.80; N, 4.76. Found: C, 73.04; H,5.88; N, 4.64.

Step B Preparation of4-hydroxy-3-methyl-5-propyl-2-(4-pyridylmethyl)-benzofuran

A mixture of 4 hydroxy 3 methyl 5 propyl-2 -(isonicotinoyl)-benzofuran(1.5 g; 5.2mmoles), potassium hydroxide pellets (2 g; 37mmoles),ethylene glycol (25 ml) and 99% hydrazine (0.8 ml) was heated withstirring at 130° C. for 1 hour and at 155° C. for 2 hours. The mixturewas cooled and acidified with 20% citric acid solution. The mixture wasextracted using 20% ethyl acetate in diethyl ether. The organic layerwas dried (Na₂ SO₄), filtered, concentrated, and chromatographed toobtain 1 g of the title compound which was then recrystallized fromethyl acetate.

m.p. 161°-163° C.

Calcd for C₁₈ H₁₉ NO₂ : C, 76.84; H, 6.80; N, 4.97. Found: C, 76.66; H,7.19; N, 4.90.

EXAMPLE 4 2-ethyl-4-hydroxy-3-methylbenzofuran

A mixture of 2-acetyl-4-hydroxy-3-methylbenzofuran (2 g; 10.5mmoles),potassium hydroxide pellets (4 g; 73mmoles), ethylene glycol (50 ml) and99% hydrazine (3 ml) was heated at 100° C. for 2 hours and at 180° C.for 2 hours. The mixture was acidified with excess 20% citric acidsolution and extracted with ether. The ether layer was dried (Na₂ SO₄),filtered, concentrated, and chromatographed to obtain 1.2 g of the titlecompound as an oil which crystallized from hexane.

m.p. 105°-107° C.

Calcd for C₁₁ H₁₂ O₂ : C, 74.97; H, 6.86. Found: C, 74.84; H, 6.76.

EXAMPLE 5 2-benzyl-4-hydroxy-3-methyl-5-propylbenzofuran

A mixture of 2-benzoyl-4-hydroxy-3-methyl-5-propylbenzofuran (1.2 g;4mmoles), potassium hydroxide pellets (1.5 g; 28mmoles), ethylene glycol(25 ml) and 99% hydrazine (0.7 ml) was heated at 135°-155° C. for 3hours. The mixture was cooled, acidified with 20% citric acid solution,extracted with ether, dried (Na₂ SO₄), filtered, concentrated, andchromatographed to obtain 650 mg of the title compound as an oil whichwas crystallized from hexane.

m.p. 40°-41° C.

Calcd for C₁₉ H₂₀ O₂ : C, 81.39; H, 7.19. Found: C, 81.46; H, 7.18.

EXAMPLE 6 5-allyl-2-ethyl-5-hydroxy-3-methylbenzofuran Step APreparation of 4 allyloxy-2-ethyl-3-methyl-benzofuran

A mixture of 2-ethyl 4 hydroxy 3 methylbenzofuran (760 mgs; 4.3mmoles),allyl bromide (1.0 g; 8.6 mmoles), anhydrous potassium carbonate (1.1 g;g; 8.6mmoles) 8.6mmoles) and acetone (50 ml) was refluxed for 4 hours.The mixture was filtered, concentrated, and chromatographed to obtain1.1 g of the title compound as an oil which was used as such in the nextstep.

Step B Preparation of 5-allyl-2-ethyl-4-hydroxy-3-methylbenzofuran

A mixture of 4-allyloxy-2-ethyl-3-methylbenzofuran (1.0 g; 4.8mmoles)and orthodichlorobenzene (40 ml) was refluxed for 4 hours. The mixturewas chromatographed to obtain 1.0 g of the title compound as an oil. Theoil was recrystallized from hexane.

m.p. 38°-40° C.

Calcd for C₁₄ H₁₆ O₂ : C, 77.74; H, 7.45. Found: C, 77.74; H, 7.06.

EXAMPLE 7 2-(1-(4-chlorophenyl)-vinyl)-3-methyl benzofuran

To a suspension of potassium t-butoxide (448 mg; 4mmoles) intetrahydrofuran (25 mL) was added methyl-triphenylphosphonium bromide(1.07 gm; 3 mmoles). The mixture was stirred for a period o 2 hours.2-(4-chlorobenzoyl)-3-methyl-4-hydroxybenzofuran (286 mg; 1mmole) intetrahydrofuran (5 ml) was added rapidly and the mixture was stirred foran additional 30 minutes at room temperature. The mixture was pouredinto 10% citric acid solution (100 ml) and was extracted withethylacetate. The organic phase was dried (Na₂ SO₄), and concentrate invacuo. The residue was chromatographed on silica gel and eluted with 10%ethylacetate in hexane to yield 210 mg (73%) of2-(1-(4-chlorophenyl)vinyl)-3-methylbenzofuran as an oil.

¹ H NMR 2.23 (s, 3H, CH₃), 5.57 (m, 2H, CH₂), 5.67 (s, 1H, OH), 6.43 (dof d, J=3 Hz, 9 Hz, H5), 7.00 (m, 2H, H6 and H7), 7.20 (s, 4H, phenylprotons).

Anal. Calcd for C₁₇ H₁₃ ClO₂ : C, 71.70; H, 4.60; Cl, 12.45 Found: C,71.54: H, 4.81; Cl, 12.35.

EXAMPLE 8 2-(3 formyl-4-methoxybenzyl)-3-methyl 4-hydroxy5-propyl-benzofuran

To a suspension of aluminium chloride (214 mg; 1.6mmole) indichloromethane (5 mL) cooled at 0° C. was added 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl benzofuran (100 mg; 0.32mmoles). Ared solution resulted. To this solution was added dropwisedichloromethylmethylether (87 (1; 0.96 mmole). There was a vigorousreaction and a color change from red to green was observed. Ice andwater was then added and the mixture was extracted with ethylacetate.The organic phase was dried (Na₂ SO₄), and concentrated in vacuo and theresidue was chromatographed on silica gel. Elution with 10% ethylacetatein hexane yielded 40 mg (37%) of 2-(3formyl-4-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran.

¹ H NMR 0.93 (t, 3H, J=7 Hz, CH₃), 1.60 (sextet, 2H, J=7 Hz, CH₂), 2.40(s, 3H, CH₃), 2.63 (t, 2H, J=7 Hz, CH₂), 3.87 (s, 3H, CH₃), 3.97 (s, 2H,CH₂), 4.90 (s, 1H, OH), 6.90 (s, 2H, H6 and H7), 6.93 (d, 1H, J=9Hz,proton ortho to methoxy), 7.40 (d of d, 1H, J=9 HZ, 3Hz, proton meta tomethoxy-0, 7.73 (d, 1H, J=3 Hz, proton ortho to formyl), 10.50 (s, 1H,formyl proton).

Anal. Calcd for C₂₁ H₂₂ O₄ : C, 74.51; H, 6.55; Found: C, 74.56: H,6.58.

EXAMPLE 92-(p-chlorobenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (a)Preparation of2-(p-chlorobenzoyl)-3-methyl-4-(chlorobenzoyloxy)-5-propyl-7-chlorobenzofuran

A solution of p-chlorobenzoyl chloride (3.5 gm; 20mmoles) in ethylenedichloride (10 mL) was added slowly to a cooled suspension of aluminiumchloride (5.36 gm; 40mmoles) in ethylene dichloride (200 mL). Afterstirring for a period of 15 minutes, 3-methyl4-hydroxy-5-propyl-7-chlorobenzofuran (1.5 gm; 7mmoles) inethylenedichloride (10 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 5 hours. It wascooled with an ice-bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the agueous phasewas extracted with methylene chloride. The organic phases were combined,dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel. Elution with 15% ethylacetate in hexaneyielded 2.63 gm (75%) of2-(p-chlorobenzoyl)-methyl-4-(p-chlorobenzoyloxy)-5-propyl-7-chlorobenzofuran,mp. 177°-182° C.

¹ H NMR 0.90 (t, J=7Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.57(s, 3H, CH₃), 2.63 (t, J=7 Hz, 2H, CH₂), 7.43 (d, J=9Hz, 1H, protonortho to chloro), 7.50 (d, J=9Hz, 1H, proton ortho to chloro), 7.60 (s,1H, H6),8.17 (d, J=9Hz, 1H, proton meta to chloro, 8.23 (d, J=9Hz, 1H,proton meta to chloro).

(b) Preparation of2-(p-chlorobenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

To an ice-cold suspension of aluminium chloride (2.1 gm, 16mmoles) inether (300 mL) was added slowly lithium aluminium hydride (2.6 gm, 68mmoles). After stirring for a period of 10 minutes,2-(p-chlorobenzoyl)-3-methyl-4-(p-chlorobenzoyloxy)-5-propyl-7-chlorobenzofuran(2.3 gm, 4.6mmoles) in ether (10 mL) was added over a period of 2minutes. The reaction mixture was stirred at room temperature for 15minutes. It was cooled with an ice bath and ice was added slowly. Whenthe vigorous reaction subsided, the organic layer was separated and theagueous phase was extracted with ether. The organic phases werecombined, washed with brine, dried (Na₂ SO₄), and concentrated in vacuo.The residue was chromatographed on silica gel. Elution with 15%ethylacetate in hexane yielded 0.30 gm (87%) of2-(p-chlorobenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran,mp.76°-77° C.

¹ H NMR 0.97 (t, J=7Hz, 3H, CH₃), 1.67 (sextet, J=7 Hz, 2H, CH₂), 2.33(s, 3H, CH₃), 2.57 (t, J=7 Hz, 2H, CH₂), 4.03 (s, 2H, CH₂), 4.80 (s, 1H,OH), 6.93 (s, 1H, H6), 7.17 (d, 2H, J=9Hz, proton ortho to chloro), 7.30(d, J=9Hz, 1H, proton meta to chloro).

EXAMPLE 10 2-(p-fluorobenzyl)-3 methyl-5 propyl-4-hydroxybenzofuran (a)Preparation of 2-hydroxy-5-allyloxyacetophenone

A mixture of 2,5-dihydroxyacetophenone (7.6 gm; 50mmoles), potassiumcarbonate (6.9 gm; 50 mmoles) and allyl bromide (6.0 gm; 50mmoles) inacetone (100 mL) was refluxed for a period of 18 hours. The reactionmixture was cooled, filtered through Celite (diatomaceous earth) andconcentrated in vacuo. The residue was chromatographed on silica gelusing 20% ethylacetate in hexane as eluent to yield 11.2 gm (97%) of2-hydroxy-5-allyloxyacetophenone, mp. 51°-53° C.

¹ H NMR 2.60 (s, 3H, CH₃), 4.52 (d,J=6Hz, 2H,OCH₂), 5.30 (m, 1H, CH),6.00 (m, 2H, CH₂, 6.83 (d, J=9 Hz, 1H, proton ortho to hydroxyl), 7.13(m, 2H, proton ortho to allyloxy).

Anal. Calcd for C₁₁ H₁₂ O₃ : C, 68.75; H, 6.25. Found: C, 68.74: H,6.53.

(b) Preparation of 2-(p-fluorobenzoyl)-3 methyl-5-allyloxybenzofuran

A mixture of 2-hydroxy-5-allyloxyacetophenone (5.0 gm; 26mmoles),potassium carbonate (3.9 gm; 28 mmoles) and p-fluorophenacylbromide (6.2gm; 28 mmoles) in methylethylketone (75 mL ) was refluxed for a periodof 22 hours. The reaction mixture was cooled, filtered through Celiteand concentrated in vacuo. The residue was chromatographed on silica gelusing 15% ethylacetate in hexane as eluent to yield 3.9 gm (48%) of2-(p-fluorobenzoyl)-3-methyl-5-allyloxybenzofuran, mp. 80°-82° C.

¹ H NMR 2.67 (s, 3H, CH₃), 4.60 (m, 2H, CH₂), 5.43 (m, 2H, CH₂), 6.13(m, 1H, CH), 7.20 (d, 3H, J= 9Hz, protons ortho to fluoro and H7), 7.27(d, J=3Hz, 1H, H4), 7.47 (d of d, J=3Hz, 9Hz, H6), 8.18 (d of d, 2H,J=5Hz, 9Hz, protons ortho to carbonyl).

Anal. Calcd for C₁₉ H₁₅ FO₃ : C, 73.53; H, 4.87; F, 6.12. Found: C,73.98: H, 4.85; F, 6.08.

(c) Preparation of2-(p-fluorobenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran

A solution of 2-(p-fluorobenzoyl)-3-methyl-5-allyloxybenzofuran (2.77gm; 9.2mmoles) in ortho dichlorobenzene (15 mL) was refluxed undernitrogen for a period of 4 hours. On cooling, the reaction productcrystallized. Some hexane was added and the crystals were filtered,washed with hexane and air-dried to yield 2.1 gm (76%) of 2(p-fluorobenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran, mp. 164°-166° C.

¹ H NMR 2.80 (s, 3H, CH₃), 3.80 (m, 2H, CH₂), 5.07 (m, 2H, CH₂), 7.20(m, 4H, protons ortho to fluoro, H5 and H7), 8.10 (d of d, 2H, J=5Hz,9Hz, protons ortho to carbonyl).

Anal. Calcd for C₁₉ H15FO₃ : C, 73.53; H, 4.87; F, 6.12. Found: C,73.53: H, 4.84; F, 6.33.

(d) Preparation of2-(p-fluorobenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran

A solution of 2-(p-fluorobenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran(1.5 gm; 4.8mmoles) in ethanol (50 mL) was hydrogenated in a Parrapparatus in presence of 10% palladium on carbon. The catalyst wasremoved by filtration and the filtrate was concentrated to dryness. Theresidue was chromatographed on silica gel using 20% ethylacetate inhexane as eluent to yield 600 mg (42%) of2-(p-fluorobenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp 121°-123°C.

¹ H NMR 0.97 (t, 3H, J=7Hz, CH₃), 1.63 (sextet, 2H, J=7Hz, CH₂), 2.27(s, 3H, CH₃), 2.83 (t, 2H, J=7 Hz, CH₂), 3.93 (s, 2H, CH₂), 4.40 (s, 2H,CH₂), 6.90 (m, 6H, aromatic protons).

Anal. Calcd for C₁₉ H₁₉ FO₂ : C, 76.48; H, 6.41; F, 6.36. Found: C,76.11; H, 6.48; F, 6.55.

EXAMPLE 11 2-(4-hydroxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran

Under nitrogen, ethanethiol (3.1 gm; 50 mmoles) was added dropwise over5 minutes to a mixture of 99% sodium hydride (1.2 gm; 50mmoles) indimethylformamide (100 mL). After stirring for 15 minutes, a solution of2-(4-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (2.1 gm;6.7mmoles) in dimethylformamide (DMF) (25 mL) was added in one portion.The mixture was refluxed for 1.5 hours, cooled, acidified with 20%citric acid and extracted with ether. The ether solution was washed withwater, dried (Na₂ SO₄), filtered, and concentrated in vacuo. Theresulting oil crystallised on standing at room temperature overnight.The crystals were slurried with hexane, filtered, washed with hexane,and air dried to yield2-(4-hydroxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp. 138°-142°C.

¹ H NMR 1.03 (t, 3H, J=7Hz, CH₃), 1.67 (sextet, 2H, J=7Hz, CH₂), 2.37(s, 3H, CH₃), 2.90 (t, 2H, J=7 Hz, CH₂), 3.80 (s, 3H, CH₃), 3.97 (s, 2H,CH₂), 4.50 (s, 2H, CH₂), 6.53 (d, 1H, J=9 Hz, H6), 6.80 (d, 2H, J=9Hz,protons ortho to methoxy), 7.07 (d, 1H, J=9 Hz, H7) 7.20 (d, 2H, J=9 Hz,protons meta to methoxy).

Anal. Calcd for C₁₉ H₂₀ O₃ : C, 77.00; H, 6.80. Found: C, 77.64: H,6.66.

EXAMPLE 12 2 (p methoxybenzyl)-3-methyl4-hydroxy-5-chloro-7-propylbenzofuran (a) Preparation of2-hydroxy-3-chloro-6-allyloxyacetophenone

A mixture of 2,6-dihydroxy-3-chloroacetophenone (1.2 gm; 6.2mmoles),potassium carbonate (8.55 mg; 6.2mmoles) and allyl bromide (562 E1; 6.5mmoles) in acetone (30 mL) was refluxed for a period of two hours. Thereaction mixture was cooled, filtered through Celite, and concentratedin vacuo. The residue was chromatographed on silica gel using 20%ethylacetate in hexane as eluent to yield 627 mg (45%) of2-hydroxy-3-chloro-6-allyloxyacetophenone.

¹ H NMR 2.74 (s, 3H, CH₃), 4.55 (d,J=6Hz, 2H,OCH₂), 5.40 (m, 2H, CH₂),6.10 (m, 1H, CH), 6.76 (d, J=9 Hz, 1H,H5), 7.43 (d,J=9Hz, 1H, H4).

(b) Preparation of 2-(pmethoxybenzoyl)-3-methyl-4-allyloxy-5-chlorobenzofuran

A mixture of 2-allyloxy-3-chloro-6-hydroxyacetophenone (587 mg;2.6mmoles), potassium carbonate (357 mg; 2.6mmoles) and pmethoxyphenacyl bromide (590 mg; 2.6mmoles) in acetone (15 mL ) wasrefluxed for a period of 18 hours. The reaction mixture was cooled,filtered through Celite, and concentrated in vacuo. The residue waschromatographed on silica gel using 20% ethylacetate in hexane as eluentto yield 2-(p methoxybenzoyl)-3-methyl-4-allyloxy-5-chlorobenzofuran.

¹ H NMR 2.73 (s 3H, CH₃), 3.88 (s, 3H, CH₃), 4.62 (d, 2H,J=6 Hz, CH₂),5.40 (m, 2H, CH₂), 6.16 (m, 1H, CH₂), 7.00 (d, 2H, J=9 Hz, protons orthoto methoxy), 7.23 (d, J=9Hz, 1H, H6), 7.41 (d, J=9 Hz, 1H, H5), 8.08 (d,2H, J=9Hz, protons ortho to carbonyl).

(c) Preparation of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-allyl-benzofuran

A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-allyloxy-5-chlorobenzofuran(400 mg; 1.12mmoles) in ortho-dichlorobenzene (15 mL) was refluxed undernitrogen for 1.5 hours. The reaction mixture was cooled to roomtemperature and purified by chromatography on silica gel using 20%ethylacetate as eluent to yield 110 mg (27%) of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-allylbenzofuran.

¹ H NMR 2.79 (s 3H, CH₃), 3.54 (d, 2H,J=6 Hz, CH₂), 3.90 (s, 3H, CH₃),5.15 (m, 2H, CH₂), 5.96 (m, 1H, CH₂), 6.96 (d, 2H, J=9 Hz, protons orthoto methoxy), 7.17 (s, 1H, H6), 8.12 (d, 2H, J=9Hz, protons ortho tocarbonyl).

(d) Preparation of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran

A solution of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-allylbenzofuran (110mg; 0.31mmole) in ethanol (15 mL) was hydrogenated in a Parr apparatusat 20 psi in the presence of 5% palladium on charcoal. The catalyst wasfiltered off and the filtrate was evaporated in vacuo to yield 110 mg of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran.

¹ H NMR 0.93 (t, J=7Hz, 3H, CH₃), 1.70 (sextet, J=7 Hz, 2H, CH₂), 2.38(s, 3H, CH₃), 2.76 (t, J=7 Hz, 2H, CH₂), 2.79 (s, 3H, CH₃), 3.90 (s, 3H,CH₃), 5.80 (s, 1H, OH), 7.00 (d, J=9Hz, 2H, protons ortho to methoxy),7.15 (s, 1H, H6 ), 8.10 (d, J=9Hz, 2H, proton meta to methoxy).

(e) Preparation of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran

A solution of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran (90mg; 0.25 mmole), hydrazine (80 μl) and potassium hydroxide (98 mg) inethylene glycol (2 mL) was heated at 145° C. for a period of 5 hours.The reaction mixture was cooled, poured in water, and extracted withether. The organic phase was washed with 20% citric acid, with brine,dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel using 20% ethylacetate in hexane as eluentto yield 47 mg (50%) of 2-(p-methoxybenzyl)3-methyl-4hydroxy-5-chloro-7-propylbenzofuran.

¹ H NMR 0.93 (t, J=7Hz, 3H, CH₃), 1.66 (sextet, J=7 Hz, 2H, CH₂), 2.36(s, 3H, CH₃), 2.70 (t, J=7 Hz, 2H, CH₂), 3.78 (s, 3H, CH₃), 4.00 (s, 2H,CH₂), 5.50 (s, 1H, OH), 6.84 (d, J=9Hz, 2H, protons ortho to methoxy),6.91 (s, 2H, H6 ), 7.15 (d, J=9Hz, 2H, proton meta to methoxy).

EXAMPLE 13 2-(p-methoxybenzyl)-3-methyl-6-hydroxy-7-propylbenzofuran (a)Preparation of 4-benzyloxy-3-propyl-2-hydroxyacetophenone

A mixture of 2,4 dihydroxy-3-propyl-aceto phenone (5.8 gm; 30mmoles),potassium carbonate (8.3 gm; 60mmoles) and benzylbromide (5.6 gm;33mmoles) in methylethylketone (60 mL ) was refluxed for a period of 4hours. The reaction mixture was cooled, filtered through Celite, andconcentrated in vacuo. The residue crystallized on stirring with hexane.It was filtered, washed with hexane, and air dried to yield 6.67 gm(78%) 4-benzyloxy-3-propyl-2-hydroxyacetophenone.

(b) Preparation of2-(p-methoxybenzoyl)-3-methyl-6-benzyloxy-7-propylbenzofuran

Sodium hydride (0.66 gm; 27.5mmoles) was added to an ice-cold mixture of4-benzyloxy-3-propyl-2-hydroxyacetophenone (6.4 gm, 22.5mmoles) anddimethylformamide (64 mL). After stirring for 30 minutes, more sodiumhydride (0.4 gm, 17.5mmoles) was added, followed by p-methoxyphenacylbromide (2.91 gm, 12.7mmoles). The reaction was stirred for 24 hours atroom temperature. The mixture was poured on ice and a slight excess ofhydrochloric acid was added. The resulting mixture was extracted withether. The organic phase.was separated, washed with water, dried (Na₂SO₄), and concentrated in vacuo. The residue crystallized from methanol.The solid was filtered, washed with methanol, and air-dried to yield2-(p-methoxybenzoyl)-3-methyl 6-benzyloxy-7-propylbenzofuran, mp.105°-106° C.

(c) Preparation of2-(p-methoxybenzyl)-3-methyl-6-benzyloxy-7-propylbenzofuran

A solution of2-(p-methoxybenzoyl)-3-methyl-6-benzyloxy-7-propylbenzofuran (1.04 gm,2.5 mmoles) in ethanol (100 mL) was hydrogenated in a Parr hydrogenatorin the presence of 10% palladium on charcoal for a period of 24 hours.The catalyst was filtered off and the filtrate was concentrated invacuo. The residue was purified by chromatography on silica gel andeluted with 25% ethylacetate in hexane to yield 110 mg of2-(p-methoxybenzyl)-3-methyl-6-hydroxy-7-propylbenzofuran.

¹ H NMR 0.97 (t, 3H, J=9Hz, CH₃), 1.63 (sextet, 2H, J=7Hz, CH₂), 2.17(s, 3H, CH₃), 2.80 (t, 2H, J=7 Hz, CH₂), 3.80 (s, 3H, CH₃), 4.00 (s, 2H,CH₂), 4.63 (s, 1H, OH), 6.70 (d, 1H, J=9Hz, H5), 6.83 (d, 2H, J=9Hz,protons ortho to methoxy), 7.13 (d, 1H, J=9Hz, H4), 7.17 (d, 2H,J=9Hz,protons meta to methoxy)

EXAMPLE 142-(p-methoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-fluorobenzofuran

A solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.10gm, 0.3 mmoles), acetic anhydride (0.5 mL) and triethylamine (0.7 mL) intetrahydrofuran (15 mL) was stirred at room temperature overnight. Thevolatiles were removed in vacuo and the residue was purified bychromatography on silica gel and eluted with 15% ethylacetate in hexaneto yield 90 mg (80%) of2-(p-methoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-fluorobenzofuran, mp.85°-88° C.

¹ H NMR 0.97 (t, 3H, J=9Hz, CH₃), 1.53 (sextet, 2H, J=7Hz, CH₂), 2.17(s, 3H, CH₃), 2.40 (s, 3H, CH₃), 2.53 (t, 2H, J=7Hz, CH₂), 3.77 (s, 3H,CH₃), 3.98 (s, 2H, CH₂), 6.73 (m, 3H, H6 and protons ortho to methoxy),7.13 (d, 2H, J=9Hz, protons meta to methoxy).

EXAMPLE 152-(p-methoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran

A solution of 2 (p-methoxybenzyl) 3 methyl 4-hydroxy 5-propyl 7chlorobenzofuran (0.10 gm, 0.29 mmoles), acetic anhydride (0.5 mL) andtriethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at roomtemperature overnight. The volatiles were removed in vacuo. The residuewas purified by chromatography on silica gel and eluted with 15%ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxybenzyl)-3-methyl-4-acetoxy-5-propyl 7-chlorobenzofuran, mp. 119°-120° C.

¹ H NMR 0.97 (t, 3H, J=9Hz, CH₃), 1.53 (sextet, 2H, J=7Hz, CH₂), 2.20(s, 3H, CH₃), 2.40 (s, 3H, CH₃), 2.53 (t, 2H, J=7Hz, CH₂), 3.80 (s, 3H,CH₃), 4.00 (s, 2H, CH₂), 6.80 (d, 2H, J=9Hz, protons ortho to methoxy),7.07 (s, 1H, H6), 7.10 (d, 2H, J=9Hz, protons meta to methoxy).

EXAMPLE 16 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-acetoxybenzofuran

A solution of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxy-benzofuran(1.2 gm, 3.87mmoles), acetic anhydride (0.5 mL) and triethylamine (1.0mL) in tetrahydrofuran (15 mL) was stirred at room temperatureovernight. The volatiles were removed in vacuo. The residue was purifiedby chromatography on silica gel and eluted with 15% ethylacetate inhexane to yield 1.2 gm (79%) of 2-(p-methoxybenzyl)-3-methyl-4-propyl5-acetoxybenzofuran, mp. 39°-41° C.

¹ H NMR 1.00 (t, 3H, J=9Hz, CH₃), 1.57 (sextet, 2H, J=7Hz, CH₂), 2.28(s, 3H, CH₃), 2.30 (s, 3H, CH₃), 2.78 (t, 2H, J=7Hz, CH₂), 3.73 (s, 3H,CH₃), 4.00 (s, 2H, CH₂), 6.80 (d, 1H, J=9Hz, H6), 6.83 (d, 2H, J=9Hz,protons ortho to methoxy), 7.10 (d, 2H, J=9Hz, protons meta to methoxy),7.17 (d, 1H, J=9Hz, H7).

EXAMPLE 172-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-fluorobenzofura

A solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.10gm, 0.3 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (0.7 mL)in tetrahydrofuran (15 mL) was stirred at room temperature overnight.The volatiles were removed in vacuo. The residue was purified bychromatography on silica gel and eluted with 15% ethylacetate in hexaneto yield 90 mg (80%) of2-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-fluorobenzofuran,mp. 85°-88° C.

¹ H NMR 0.97 (t, 3H, J=9Hz, CH₃), 1.53 (sextet, 2H, J=7Hz, CH₂), 2.17(s, 3H, CH₃), 2.40 (s, 3H, CH₃), 2.53 (t, 2H, J=7Hz, CH₂), 3.77 (s, 3H,CH₃), 3.98 (s, 2H, CH₂), 6.73 (m, 3H, H6 and protons ortho to methoxy),7.13 (d, 2H, J=9Hz, protons meta to methoxy).

EXAMPLE 182-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl--7-chlorobenzofuran

A solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10gm, 0.29 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0mL) in tetrahydrofuran (15 mL) was stirred at room temperatureovernight. The volatiles were removed in vacuo. The residue was purifiedby chromatography on silica gel and eluted with 15% ethylacetate inhexane to yield 100 mg (91%) of 2 (p-methoxybenzyl) 3 methyl 4ethoxycarbonyloxy 5 -5-propyl 7 chlorobenzofuran, mp. 99°-100° C.

¹ H NMR 0.97 (t, 3H, J=9Hz, CH₃), 1.53 (sextet, 2H, J=7Hz, CH₂), 2.20(s, 3H, CH₃), 2.53 (t, 2H, J=7 Hz, CH₂), 3.78 (s, 3H, CH₃), 3.98 (s, 3H,CH₃), 4.07 (s, 2H, CH₂), 6.87 (d, 2H, J=9 Hz, protons ortho to methoxy),7.17 (s, 1H, H6), 7.20 (d, 2H, J=9Hz, protons meta to methoxy).

EXAMPLE 192-(p-methoxybenzyl)-3-methyl-4-propyl-5-ethoxycarbonyloxy-benzofuran

A solution of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran(1.2 gm, 3.87mmoles), ethyl chloroformate (0.1 mL) and triethylamine(1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperatureovernight. The volatiles were removed in vacuo. The residue was purifiedby chromatography on silica gel and eluted with 15% ethylacetate inhexane to yield 1.2 gm (79%) of 2 (p-methoxybenzyl)3-methyl-4-propyl-5-ethoxycarbonyloxybenzofuran, mp. 51°-53° C.

¹ H NMR 1.00 (t, 3H, J=9Hz, CH₃), 1.60 (sextet, 2H, J=7Hz, CH₂), 2.33(s, 3H, CH₃), 2.83 (t, 2H, J=7 Hz, CH₂), 3.80 (s, 3H, CH₃), 3.93 (s, 3H,CH₃), 4.00 (s, 2H, CH₂), 6.80 (d, 1H, J=9Hz, H6), 6.90 (d, 2H, J=9Hz,protons ortho to methoxy), 7.18 (d, 2H, J=9Hz, protons meta to methoxy),7.23 (d, 1H, J=9Hz, H7).

EXAMPLE 202-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-bromobenzofuran

A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran(1 gm; 3.22mmoles) in methylene chloride (30 mL) was cooled at 0° C. andbromine (0.52 gm; 3.22mmoles) in methylene chloride (10 mL) was addeddropwise. The reaction mixture was stirred for 15 minutes. The reactionmixture was washed with a saturated sodium bicarbonate solution, dried(Na₂ SO₄), and concentrated in vacuo. The residue was purified bypreparative TLC, eluting with 15% ethylacetate in hexane to yield2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-bromobenzofuran, mp.110°-112° C.

¹ H NMR 0.98 (t, J=7Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.36(s, 3H, CH₃), 2.55 (t, J=7 Hz, 2H, CH₂), 3.78 (s, 6H, CH₃), 4.00 (s, 2H,CH₂), 4.97 (s, 1H, OH), 6.83 (d, J=9Hz, 2H, protons ortho to methoxy),7.07 (s, 1H, H6), 7.17 (d, J=9Hz, 2H, proton meta to methoxy).

EXAMPLE 21 2-(p-methoxybenzyl)-3,7-dimethyl-4-hydroxy-5-propylbenzofuran(a) Preparation of2-(p-methoxybenzyl)-3-methyl-4-4-hydroxy-5-propyl-7-dimethylaminomethylbenzofuran

A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran(155 mg gm; 0.5mmole) in methylene chloride (2 mL) was reacted withEschenmoser's salt (dimethyl methylene-ammonium iodide) (105 mg;0.5mmole) overnight at room temperature. The reaction mixture wasconcentrated in vacuo. The residue was taken up in ethylacetate,potassium carbonate was added and the mixture was stirred for a periodof 15 minutes. The solids were separated and the ethylacetate solutionwas evaporated to yield 228 mg of2-(p-methoxybenzyl)--3-methyl-4-hydroxy-5-propyl-7-dimethylaminomethylbenzofuran.

¹ H NMR 0.98 (t, J=7Hz, 3H, CH₃), 1.70 (sextes, J=7 Hz, 2H, CH₂), 2.33(s, 6H, CH₃ N), 2.43 (s, 3H, CH₃), 2.63 (t, J=7 Hz, 2H, CH₂), 3.73 (s,2H, CH₂ N), 3.83 (s, 3H, CH₃ O), 4.07 (s, 2H, CH₂), 4.90 (s, 1H, OH),6.90 (d, J=9Hz, 2H, protons ortho to methoxy), 6.93 (s, 1H, H6), 7.23(d, J=9Hz, 2H, proton meta to methoxy).

(b) Preparation of2-(p-methoxybenzyl)-3,7-dimethyl-4-hydroxy-5-propylbenzofuran

To a solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-dimethylaminomethylbenzofuran(0.2 gm; 0.54mmole) in ethanol (5 mL) was added sodium borohydride (0.2gm, 5.45mmoles) and the reaction mixture was refluxed for 10 minutes.The reaction mixture was cooled, poured in a saturated solution ofammonium chloride, and extracted with ether. The organic phase waswashed with with brine, dried (Na₂ SO₄), and concentrated in vacuo. Theresidue was chromatographed on silica gel using 20% ethylacetate inhexane as eluent to yield 160 mg (91%) of2-(p-methoxybenzyl)-3,7-dimethyl-4-hydroxy-5-propylbenzofuran, mp.102°-104° C.

¹ H NMR 0.98 (t, J=7Hz, 3H, CH₃), 1.67 (sextet, J=7 Hz, 2H, CH₂), 2.37(s, 3H, CH₃), 2.43 (s, 3H, CH₃), 2.63 (t, J=7 Hz, 2H, CH₂), 3.78 (s, 3H,CH₃), 4.00 (s, 2H, CH₂), 4.60 (s, 1H, OH), 6.73 (s, 1H, H6), 6.83 (d,J=9Hz, 2H, protons ortho to methoxy), 7.20 (d, J=9Hz, 2H, proton meta tomethoxy).

Anal. Calcd for C₂₁ H₂₄ O₃ : C, 77.73; H, 7.46; Found: C, 77.88: H,7.55.

EXAMPLE 22 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5,7-dipropylbenzofuran(a) Preparation of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5,7-dipropylbenzofuran

A mixture of 2,6-dihydroxy-3,5-dipropylacetophenone (3.38 gm;14.3mmoles), potassium carbonate (1.97 gm; 14.3mmoles) andp-methoxy-phenacylbromide (3.27 gm; 14.3mmoles) in acetone (50 mL) wasrefluxed for a period of eighteen hours. The reaction mixture wascooled, filtered through Celite, and concentrated in vacuo. The residuewas chromatographed on silica gel using 20% ethylacetate in hexane aseluent to yield 0.40 gm (8%) of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5,7-dipropylbenzofuran, mp.119°-121° C.

¹ H NMR 0.93 (t, J=7Hz, 3H, CH₃), 0.98 (t, J=7Hz, 3H, CH₃), 1.66(sextet, J=7Hz, 4H, CH₂), 2.60 (t, J=7 Hz, 2H, CH₂), 2.70 (t, J=7 Hz,2H, CH₂), 2.80 (s, 3H, CH₃), 3.90 (s, 3H, CH₃), 5.00 (s, 1H, OH), 6.93(s, 1H, H6), 6.98 (d, J=9Hz, 2H, proton ortho to methoxy), 8.13 (d, J=9Hz, 2H, proton ortho to carbonyl).

(b) Preparation of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5,7-dipropylbenzofuran

A mixture of 2 (p-methoxybenzoyl)-3methyl-4-hydroxy-5,7-dipropylbenzofuran (0.30 gm; 0.80 mmoles), 99%hydrazine (0.2 mL), potassium hydroxide (0.40 gm; 7mmoles) in ethyleneglycol (10 mL) was heated at 140° C. for a period of 2.5 hours and at195° C. for one hour. The reaction mixture was cooled, poured intowater, and extracted with ethylacetate. The organic phase was washedwith 20% citric acid, with brine, dried (Na₂ SO₄), and concentrated invacuo. The residue was chromatographed on silica gel using 20%ethylacetate in hexane as eluent to yield 140 mg (50%) of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5,7-dipropylbenzofuran, mp.70°-72° C.

¹ H NMR 0.93 (t, J=7Hz, 3H, CH₃), 0.98 (t, J=7Hz, 3H, CH₃), 1.63(sextet, J=7Hz, 2H, CH₂), 1.68 (sextet, J=7Hz, 2H, CH₂), 4H, CH₂), 2.38(s, 3H, CH₃), 2.60 (t, J=7Hz, 2H, CH₂), 2.68 (t, J=7Hz, 2H, CH₂), 3.77(s, 3H, CH₃), 3.93 (s, 2H, CH₂), 4.70 (s, 1H, OH), 6.70 (s, 2H, H6 andH7), 6.80 (d, J=9Hz, 2H, proton ortho to methoxy), 6.90 (s, 1H, H6),7.17 (d, J=9 Hz, 2H, proton meta to methoxy).

Anal. Calcd for C₂₀ H₂₂ O₃ : C, 78.37; H, 8.00; Found: C, 77.82: H,7.70.

EXAMPLE 232-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (a)Preparation of 2,6-dihydroxy-3-propyl-5-chloroacetophenone

A mixture of 2,6-dihydroxy-3-propylacetophenone (40 gm, 0.206 mole) andN-chlorosuccinimide (40 gm; 0.300 mole) in methylene chloride (3 liters)was stirred at room temperature for a period of two days. The reactionmixture was poured onto a 3 liter fritted disk funnel filled with silicagel and elution was carried out with methylene chloride. Evaporation ofthe filtrate yielded 2,6-dihydroxy-3-propyl-5-chloroacetophenone; m.p.:64°-65° C.

¹ H NMR 0.93 (t, J=7Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.53(t, J=7 Hz, 2H, CH₂), 2.73 (s, 3H, CH₃), CH₂), 6.33 (s, 1H, proton orthoto chloro 13.13 (s, 1H, OH).

(b) Preparation of2-carboethoxymethoxy-6-hydroxy-3-chloro-5-propylacetophenone

A mixture of 2,6-dihydroxy-5-chloro-3-propylacetophenone (38.5 gm, 0.169mole), ethyl bromoacetate (18.6 ml; 0.169 mole) and potassium carbonate(23.24 gm; 0.169 mole) in acetone (3 liters) was refluxed for a periodof 2.5 hours. The reaction mixture was filtered through Celite and thefiltrate was concentrated in vacuo. The residue was purified bychromatography on silica gel and eluted with 5% ethyl acetate in hexaneto yield 2-carboethoxymethoxy-6-hydroxy-3-chloro-5-propylacetophenone.

¹ H NMR 0.93 (t, J=7Hz, 3H, CH₃), 1.30 (t, J=7Hz, 3H, CH₃, 1.63 (sextet,J=7Hz, 2H, CH₂), 2.57 (t, J=7 Hz 2H CH₂). 2.77 (s, 3H, CH₃). CH₂),4.27(g, J=7 Hz, 2H, CH₂ O), 4.73 (s, 2H, CH₂), 7.23 (s, 1H, proton ortho tochloro),12.50 (s, 1H, OH).

(c) Preparation of2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran.

To a solution of2-carboethoxymethoxy-6-hydroxy-3-chloro-5-propylacetophenone (43 gm;0.136 mole) in freshly distilled absolute ethanol (1.2 liter) wasbrought to reflux and a 1M solution of sodium ethoxide (273 mL; 0.273mole) was added rapidly. The reaction mixture was refluxed for a periodof 1 hour. It was cooled to room temperature and poured into 0.5Nhydrochloric acid and extracted with ethylacetate. The organic phase wasdried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 15% ethylacetate in hexaneto yield 22.0 gm of 2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran; m.p.: 165°-166°.

¹ H NMR 1.00 (t, J=7 Hz, 3H, CH₃), 1.25 (t, J=7Hz, 3H, CH₃, 1.63(sextet, J=7 Hz, 2H, CH₂), 2.57 (t, J=7 Hz, 2H, CH₂), 2.76 (s, 3H, CH₃),CH₂),4.43 (g, J=7 Hz, 2H, CH₂ O), 5.19 (s, 1H, OH), 7.15 (s, 1H, protonortho to chloro), 5.19 (s, 1H, OH).

3-methyl-4-hydroxy-5-propyl-7-chlorobenzo furan was also obtained; m.p.:49-50° C.

¹ H NMR 0.97 {t, J=7 Hz, 3H, CH₃), 1.60 (sextet, J=7 Hz, 2H, CH₂), 2.32(s, 3H, CH₃), CH₂), 2.50 (t, J=7 Hz, 2H, CH₂), 4.97 (s, 1H, OH), 6.93(s, 1H, proton ortho to chloro), 7.20 (s, 1H, H2).

Anal. Calcd for C₁₂ H₁₃ ClO₂ : C, 64.58; H, 6.20; Cl, 15.72. Found: C,64.14: H, 5.79; Cl, 15.81.

(d) Preparation of 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofurancarboxylic acid

To a solution of2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (22 gm,0.074 mole) in methanol (1.2 liter) was added 2N sodium hydroxide (120mL) and the resulting solution was refluxed for a period of 6 hours. Thereaction mixture was concentrated in vacuo. The residue was acidifiedwith 3N hydrochloric acid and then extracted with ethylacetate. Theorganic phase was dried (Na₂ SO₄), concentrated in vacuo, and3-methyl-4-hydroxy-5-propyl-7-chlorobenzofurancarboxylic acid (17 gm;88%) was isolated by filtering the solid after suspending in hexane;m.p.: 200°-203° C.

¹ H NMR 0.97 (t, J=7 Hz, 3H, CH₃), 1.60 (sextet, J=7 Hz, 2H, CH₂), 2.60(t, J=7 Hz, 2H, CH₂), 2.80 (s, 3H, CH₃), 7.33 (s, 1H, proton ortho tochloro), 7.60 (s, 1H, OH).

(e) Preparation of 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

A mixture of 3-methyl-4-hydroxy-5-propyl--7-chlorobenzofuran carboxylicacid (0.93 gm; 3.7 mmoles), toluene (25 mL), 6N hydrochloric acid (20mL), 10N HCl (100 mL) and acetic acid (30 ml) was refluxed for a periodof 18 hours. The two phases were separated and the organic phase wasdried (Na₂ SO₄), and concentrated in vacuo to yield3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.62 gm; 80%), identicalto the product obtained from the cyclisation reaction described above inStep C.

(f) Preparation of 2-(p-methoxybenzoyl)-3-methyl4-(p-methoxybenzoyloxy)-5-propyl-7-chlorobenzofuran

A solution of p-anisoyl chloride (3.5 gm; 20.5mmoles) in ethylenedichloride (10 mL) was added slowly to a cooled suspension of aluminiumchloride (4.0 gm; 30mmoles) in ethylene dichloride (100 mL). Afterstirring for a period of 10 minutes,3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1.14 gm; 5 mmoles) indichloroethylene (5 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 1 hour. It wascooled with an ice bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separatd and the agueous phasewas extracted with methylene chloride. The organic phases were combined,dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 10% ethylacetate in hexaneto yield 1.92 gm (78%) of2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)5-propyl-7-chlorobenzofuran,mp.103°-105° C.

¹ H NMR 0.97 (t, J=7 Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.55(s, 3H, CH₃), 2.63 (t, J=7 Hz, 2H, CH₂). 3.93 (s, 6H, CH₃). 7.07 (d.J=9Hz. lH proton ortho to methoxy). 7.13 (d, J=9Hz. 1H, proton ortho tomethoxy), 8.23 (d, J=9 Hz, 1H, proton ortho to methoxy), 7.27 (d, J=9Hz, 1H, proton ortho to methoxy).

Anal. Calcd for C₂₀ H₂₁ ClO₃ : C, 69.66; H, 6.13; Cl, 10.28. Found: C,69.80: H, 6.18; Cl, 10.23.

(g) Preparation of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

To an ice cold suspension of aluminium chloride (467 mg, 3.5mmoles) inether (100 mL) was added slowly lithium aluminium hydride (570 mg, 15mmoles). After stirring for a period of 10 minutes,2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (491mg, 1mmole) in ether (10 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 10 minutes. It wascooled with an ice-bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the agueous phasewas extracted with ether. The organic phases were combined, washed withbrine, dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 10% ethyl acetate inhexane to yield 0.30 gm (87%) of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp.103-105 C.

¹ H NMR 1.00 (t, J=7 Hz, 3H, CH₃), 1.64 (sextet, J=7 Hz, 2H, CH₂), 2.39(s, 3H, CH₃), 2.57 (t, J=7 Hz, 2H, CH₂), 3.79 (s, 6H, CH₃), 4.03 (s, 2H,CH₂), 6.84 (d, J=9 Hz, 1H, proton ortho to methoxy), 6.93 (s, 1H, protonortho to chloro), 7.18 (d, J=9 Hz, 1H, proton meta to methoxy).

Anal. Calcd for C₂₀ H₂₁ ClO_(3:) C, 69.66; H, 6.13; Cl, 10.28. Found: C,69.80: H, 6.18; Cl, 10.23.

Following the procedure of Example 23, step (e), the compounds of Table23-1 were prepared from the appropriate precursor acids described inU.S. Ser. No. 661,645, filed October 17, 1984, a CIP of which has nowissued as U.S.Pat. No. 4,663,347.

                  TABLE 23-1                                                      ______________________________________                                        R1   R2      R3        X     Y      Y1  M.P. (°C.)                     ______________________________________                                        Me   H       5,6-OCH.sub.2 O                                                                         O     H      H   48-50                                 Me   H       4-OMe     O     7-Pr   H   OIL                                   Me   H       7-OH      O     H      H   90-91                                 Me   H       4-OH      O     7-Pr   H   65-66                                 Me   H       5-OH      O     H      H   84-5                                  Me   H       4-OH      O     5-allyl                                                                              H   OIL                                   Pr   H       4-OH      O     H      H   35-36                                 Pr   H       4-allyl   O     H      H   OIL                                   Pr   H       4-OH      O     5-allyl                                                                              H   OIL                                   Me   H       5-Oallyl  O     H      H   OIL                                   Me   H       5-OH      O     4-allyl                                                                              H   65-67                                 Me   H       5-OH      O     4-Pr   H   83-85                                 Me   H       4-OH      O     5-Pr   H   35-36                                 C.sub.6 H.sub.5                                                                    H       4-OH      O     H      H   OIL                                   Me   H       4-OH      O     H      H   110-112                               ______________________________________                                    

EXAMPLE 24 2-(p-methoxybenzyl)-3-methyl-5-hydroxybenzofuran (a)Preparation of2-(p-methoxybenzoyl)-3-methyl-5-(p-methoxyphenacyloxy)-benzofuran

A mixture of 2,5-dihydroxyacetophenone (2.78 gm; 18.3mmoles), potassiumcarbonate (5.06 gm; 36.6 mmoles) and p-methoxyphenacyl bromide (8.4 gm,36.8 mmoles) in acetone (100 mL) was refluxed for a period of 18 hours.The reaction mixture was cooled, filtered through Celite, andconcentrated in vacuo. The residue was taken up in a minimum volume ofacetone and the solution was left to crystallize. The crystals werefiltered, washed with cold ethylacetate, and air-dried to yield 4.0 gm(51%) of 2-(p-methoxybenzoyl)-3-methyl5-(p-methoxyphenacyloxy)-benzofuran, mp. 155°-157° C.

¹ H NMR 2.60 (s, 3H, CH₃), 3.93 (s, 6H, CH₃), 5.30 (s, 2H, CH₂), 7.00(m, 4H, protons ortho to metooxyl), 7.20 (m, 2H, H6 and H7), 8.10 (t,2H, J=9Hz, protons meta to methoxy).

Anal. Calcd for C₁₁ H₁₂ O₃ : C, 72.54; H, 5.15. Found: C, 72.57: H,5.22.

(b) Preparation of 2-(p-methoxybenzyl)-3-methyl5-hydroxybenzofuran

A mixture of2-(p-methoxybenzoyl)-3-methyl-5-(p-methoxyphenacyloxy)-benzofuran (5.35gm, 12.4 mmoles) and zinc dust (5.3 gm) in acetic acid (200 mL) wasstirred at room temperature overnight. The solids were filtered off andwashed with some ethylacetate. The filtrate was concentrated in vacuoand the residue was chromatographed on silica gel using 20% ethylacetatein hexane as eluent to yield 0.85 gm (26%) of2-(p-methoxybenzyl)3-methyl5-hydroxybenzofuran, mp. 128°-131° C.

¹ H NMR 2.17 (s, 3H, CH₃), 3.70 (s, 3H, CH₃), 3.93 (s, 2H, CH₂), 6.90(m, 7H, aromatic protons)

Anal. Calcd for C₁₇ H₁₆ O₃ : C, 76.09; H, 6.01. Found: C, 76.35; H,6.37.

EXAMPLE 252-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (a)Preparation of 2-hydroxy-6-allyloxyacetophenone

A mixture of 2,6-dihydroxyacetophenone (300 gm; 1.97 moles), potassiumcarbonate (271 gm; 1.97 moles), and allyl bromide (271 mLs; 2.25 moles)in acetone (10 liters) was refluxed for a period of 3 hours. Thereaction mixture was cooled, filtered through Celite and concentrated invacuo. The residue was chromatographed on silica gel using toluene aseluent to yield 305 gm (80%) of 2-hydroxy-6-allyloxyacetophenone, mp.54°-55° C.

¹ H NMR 2.40 (s, 3H, CH₃), 4.57 (d,J=6 Hz, 2H,OCH₂), 5.57 (m, 1H, CH),6.33 (m, 2H, CH₂, 6.62 (d, J=9 Hz, 1H, proton ortho to hydroxyl), 6.83(d,J=9 Hz, 1H, proton ortho to allyloxy), 7.72 (t, J=9 Hz, 1H, protonpara to acetyl).

Anal. Calcd for C₁₁ H₁₂ O₃ : C, 68.75; H, 6.25. Found: C, 68.66; H,6.54.

(b) Preparation of2,6-dihydroxy-3-allylacetophenone-2-hydroxy-5-allyloxyacetophenone (30gm; 0.156 mole) was heated under nitrogen at 190° C. for a period of 10minutes. The mixture was cooled and taken up into carbon tetrachlorideto yield 2,6-dihydroxy-3-allylacetophenone, mp 67°-68° C. inguantitative yield.

¹ H NMR 2.77 (s, 3H, CH₃), 3.37 (d,J=6 Hz, 2H,OCH₂), 5.37 (m, 1H,CH),6.00 (m, 2H, CH₂, 6.33 (d, J=9 Hz, 1H, proton ortho to hydroxyl), 7.17(d,J=9 Hz, 1H, proton meta to hydroxy).

Anal. Calcd for C₁₁ H₁₂ O₃ C, 68.75; H, 6.25. Found C, 68.90; H, 6.21.

(c) Preparation of2,6-dihydroxy-3-propylacetophenone-2,6-dihydroxy-3-allylacetophenone (30gm; 0.156 mole) dissolved in ethanol (150 mL) was hydrogenated in a Parrapparatus in presence of 5% palladium on carbon. The catalyst wasremoved by filtration and the filtrate was concentrated to dryness toyield 30 gm of 2,6-dihydroxy-3-propylacetophenone, mp. 76°-78° C.

¹ H NMR 0.97 (t, J=7 Hz, 3H, CH₃), 1.60 (sextet, J=7 Hz, 2H, CH₂), 2.53(t, J=7 Hz, 2H, CH₂), 2.73 (s, 3H, CH₃), CH₂), 6.30 (d, J=9 Hz, 1H,proton ortho to hydroxy), 7.13 (d,J=9 Hz, 1H, proton meta to hydroxy).

Anal. Calcd for C₁₁ H₁₄ O_(3:) C, 68.04; H, 7.21. Found: C, 68.05; H,7.34.

(d) Preparation of 2,6-dihydroxy-3-propyl-5-fluoroacetophenone Method1.A solution of 2,6-dihydroxy-3-propyl-acetophenone (194 mg; 1mmole) inFreon (fluoro-trichloromethane) (30 mL) was cooled at -78° C. andtrifluoromethylhypofluorite was bubbled through the solution slowly,monitoring the reaction by TLC until about half of the material hasreacted. The mixture is poured onto a silica gel column and elution with15% ethylacetate in hexane gave 40 mg of 2,6-dihydroxy3-propyl-5-fluoroacetophenone.

¹ H NMR 0.93 (t, J=7 Hz, 3H, CH₃), 1.67 (sextet, J=7 Hz, 2H, CH₂), 2.57(t, J=7 Hz, 2H, CH₂), 2.80 (s, 3H, CH₃), 6.18 (d, J=6 Hz, 1H, OH orthoto fluoro), 7.13 (d, J=11 Hz, 1H, proton ortho to fluoro). Method 2a.Preparation of 2,6-dimethoxy-3-propyl-5-fluoroacetophenone

A solution of 2,6-dimethoxy-3-propylacetophenone (21.0 gm; 94.6mmoles)in Freon (30 mL) was cooled at -78° C. and trifluoromethylhypofluoritewas bubbled through the solution slowly, monitoring the reaction by TLCuntil about 75% of the material has reacted. The mixture is poured ontoa silica gel column and elution with 15% ethylacetate in hexane gave11.1 g of 2,6-dimethoxy propyl-5-fluoroacetophenone and 9.0 gm ofunreacted 2,6-dimethoxy-3-propylacetophenone.

¹ H NMR 0.97 (t, J=7 Hz, 3H, CH₃), 1.67 (sextet, J=7 Hz, 2H, CH₂), 2.50(t, J=7 Hz, 2H, CH₂), 2.50 (s, 3H, CH₃), 3.70 (s, 3H, CH₃) 3.82 (d, J=3Hz, 3H, CHJ3), 6.90 (d, J=11 Hz, 1H, proton ortho to fluoro). 2b.Preparation of 2,6-dihydroxy-3-propyl-5-fluoroacetophenone

To a solution of 2,6-dimethoxy-3-propyl-5-fluoroacetophenone (3.0 gm;12.5mmoles) in methylene chloride (32 mL) cooled to -78° C., was addeddropwise over a period of 1 hour a 1M solution of boron tribromide (56mL; 56mmoles) The temperature was allowed to rise to room temperatureand the reaction mixture was stirred for 3 hours. It was then cooled to-78° C. and methanol (20 mL) was added rapidly. The resulting solutionwas poured in water, the phases were separated and the agueous phase wasextracted with methylene chloride. The organic phases were combined,washed with brine, dried (Na₂ SO₄), and concentrated in vacuo. Theresidue was chromatographed on silica gel and eluted with 7%ethylacetate in hexane to yield 1.5 gm (58%) of2,6-dihydroxy-3-propyl-5-fluoroacetophenone.

¹ H NMR 0.93 (t, J=7 Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.50(t, J=7 Hz, 2H, CH₂), 2.73 (s, 3H, CH₃), 5.93 (d, J=6 Hz, 1H, OH), 7.10(d, J=11 Hz, 1H, proton ortho to fluoro).

(e) Preparation of2-carboethoxymethoxy-6-hydroxy-3-propyl-5-fluoroacetophenone

A mixture of 2,6-dihydroxy-5-fluoro-3-propylacetophenone (3.5 gm,16.5mmoles), ethyl bromoacetate (2.0 ml; 18.1mmoles) and potassiumcarbonate (2.27 gm; 16.5mmoles) in acetone (1 liter) was refluxed for aperiod of 0.5 hour. The reaction mixture was filtered through Celite andthe filtrate was concentrated in vacuo to yield a residue that purifiedby chromatography on silica gel. Elution with 10 % ethyl acetate inhexane yielded 4.2 gm (86%) of 2-carboethoxymethoxy 6-hydroxy3-propyl-5-fluoroacetophenone.

¹ H NMR 0.93 (t, J=7 Hz, 3H, CH₃), 1.27 (t, J=7Hz, 3H, CH₃, 1.63(sextet, J=7 Hz, 2H, CH₂), 2.53 (t, J=7 Hz, 2H, CH₂), 2.77 (s, 3H, CH₃),CH₂),4.20 (g, J=7 Hz, 2H, CH₂ O), 4.80 (s, 2H, CH₂), 7.03 (d, J=11Hz,1H, proton ortho to fluoro).

(f) Preparation of2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran.

A solution of2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (15 gm;50.0 mmoles) in freshly-distilled absolute ethanol (0.5 liter) wasbrought to reflux and a 1M solution of sodium ethoxide (100 mL;100mmoles) was added rapidly. The reaction mixture was refluxed for aperiod of 1 hour. It was cooled to room temperature and poured into 0.5Nhydrochloric acid and extracted with ethyl acetate. The organic phasewas dried (Na₂ SO₄), concentrated in vacuo, and the residue waschromatographed on silica gel. Elution with 10% ethylacetate in hexaneyielded 9.0 gm of2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran.

¹ H NMR 1.00 (t, J=7 Hz, 3H, CH₃), 1.43 (t, J=7Hz, 3H, CH₃, 1.63(sextet, J=7 Hz, 2H, CH₂), 2.57 (t, J=7 Hz, 2H, CH₂), 2.80 (s, 3H, CH₃),CH₂),4.47 (g, J=7 Hz, 2H, CH₂ O), 4.97 (s, 1H, OH), 6.90 (s, 1H, protonortho to fluoro).

3-methyl-4-hydroxy-5-peopyl-7-fluorobenzofuran, (1.0 gm) mp. 53°-54° C.was also obtained.

¹ H NMR 1.00 (t, J=7 Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.40(d,J=2 Hz, 3H, CH₃), CH₂), 2.57 (t, J=7 Hz, 2H, CH₂), 4.73 (s, 1H, OH),6.73 (d,J=11 Hz, 1H, proton ortho to fluoro), 7.28 (d,J=2Hz, 1H, H2).

Anal. Calcd for C₁₂ H₁₃ ClO₂ : C, 69.23; H, 6.25; F, 9.13. Found: C,64.14; H, 5.79; Cl, 15.81.

(g) Preparation of3-methyl-4-hydroxy-5-propyl-7-fluorobenzofurancarboxylic acid

To a solution of2-carboethoxy-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (1.0 gm,3.6 mmoles) in methanol (100 mL) was added 2N sodium hydroxide (10 mL)and the resulting solution was refluxed for a period of 4.5 hours. Thereaction mixture was concentrated in vacuo. The residue was acidifiedwith 3N hydrochloric acid and then extracted with ethylacetate. Theorganic phase was dried (Na₂ SO₄), concentrated in vacuo, and 3 methyl-4hydroxy 5 propyl 7 -fluorobenzofuran-carboxylic acid (0.79 gm; 88%) wasisolated by filtering the solid after suspending in hexane.

¹ H NMR 0.97 (t, J=7 Hz, 3H, CH₃), 1.60 (sextet, J=7 Hz, 2H, CH₂), 2.67(t, J=7 Hz, 2H, CH₂), 2.80 (s, 3H, CH₃), 6.90 (d,J=11 Hz, 1H, protonortho to fluoro), 7.00 (s, 2H, OH).

(h) Preparation of 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran

A mixture of 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofurancarboxylicacid (0.10 gm; 0.4mmoles) and copper(20 mg) in guinoline (50 mL) wasrefluxed for a period of 2.5 hours. The two phases were separated andthe organic phase was dried (Na₂ SO₄), and concentrated in vacuo. Theresidue was purified by preparative TLC and eluted with 5% ethylacetatein hexane to yield 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (62 mg; 75%), identical to the product obtained from the cyclisation reactiondescribed above in step f.

(i) Preparation of2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)-5-propyl-7-fluorobynzofuran

A solution of p-anisoyl chloride (2.70 gm; 15.5mmoles) in ethylenedichloride (10 mL) was added slowly to a cooled suspension of aluminiumchloride (3.0 gm; 21.8mmoles) in ethylene dichloride (100 mL). Afterstirring for a period of 10 minutes,3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.79 gm; 3.8mmoles) indichloroethylene (5 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 1 hour. It wascooled with an ice-bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the agueous phasewas extracted with methylene chloride. The organic phases were combined,dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 10% ethylacetate in hexaneto yield 1.18 gm (63%) of2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)-5-propyl-7-fluorobenzofuran.

¹ H NMR 0.90 (t, J=7 Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.55(s, 3H, CH₃), 2.63 (t, J=7 Hz, 2H, CH₂), 3.90 (s, 6H, CH₃), 6.97 (d, J=9Hz, 1H, proton ortho to methoxy), 7.03 (d, J=9Hz, 1H, proton ortho tomethoxy), 8.13 (d, J=9 Hz, 1H, proton ortho to methoxy), 8.23 (d, J=9Hz, 1H, proton ortho to methoxy).

Anal Calcd for C₂₀ H₂₁ ClO_(3:) C, 69.66; H, 6.13; F, 10.28. Found: C,69.80; H, 6.18; F, 10.23.

(j) Preparation of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran

To an ice cold suspension of aluminium chloride (1.14 gm, 8.5 mmoles) inether (100 mL) was added slowly lithium aluminium hydride (1.39 gm, 36mmoles). After stirring for a period of 10 minutes,2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (1.18gm, 2.48mmoles) in ether (10mL) was added over a period of 2 minutes.The reaction mixture was stirred at room temperature for 10minutes. Itwas cooled with an ice-bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the agueous phasewas extracted with ether. The organic phases were combined, washed withbrine, dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 10% ethyl acetate inhexane to yield 0.58 gm (71%) of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran.

¹ H NMR 0.98 (t, J=7 Hz, 3H, CH₃), 1.66 (sextet, J=7 Hz, 2H, CH₂), 2.39(s, 3H, CH₃), 2.55 (t, J=7 Hz, 2H, CH₂), 3.78 (s, 6H, CH₃), 4.00 (s, 2H,CH₂), 6.67 (d, J=11 Hz, 1H, proton ortho to fluoro), 6.84 (d, 2H, protonortho to methoxy), 7.16 (d, J=9 Hz, 1H, proton meta to methoxy).

Anal. Calcd for C₂₀ H21ClO₃ : C, 73.15; H, 6.44; F, 5 78. Found: C,73.71; H, 6.45; F, 5.09.

EXAMPLE 26 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-7-propylbenzofuran (a)Preparation of 2-hydroxy-3-propyl-6-benzyloxyacetophenone

A mixture of 2,6-dihydroxy-3-propylacetophenone (5.5 gm; 28.3mmoles),potassium carbonate (3.9 gm; 31mmoles) and benzyl bromide (4.3 gm; 31mmoles) in acetone (10 liters) was refluxed for a period of twentyhours. The reaction mixture was cooled, filtered through Celite, andconcentrated in vacuo. The residue was chromatographed on silica gelusing 10% ethylacetate in hexane as eluent to yield 5.6 gm (70%) of2-hydroxy-3-propyl-6-benzyloxyacetophenone.

¹ H NMR 0.93 (t, 3H, J=7 Hz, CH₃), 1.60 (sextet, 2H, J=7 Hz, CH₂), 2.60(t, 2H, J=7 Hz, CH₂), 2.67 (s, 3H, CH₃), 5.13 (s, 2H, CH₂), 6.40 (d, 1H,J=9Hz, H5), 7.23 (d, 1H, J=9 Hz, H4), 7.40 (s, 5H, phenyl protons).

(b) Preparation of2-(p-methoxybenzoyl)-3-methyl-4-benzyloxy-7-propyl-benzofuran.

A mixture of 2-hydroxy-3-propyl-6-benzyloxyacetophenone (1.0 gm; 3.52mmoles), potassium carbonate (0.81 gm; 3.82 mmoles) andp-methoxyphenacyl bromide (0.54 gm, 3.80 mmoles) in methylethylketone(40 mL) was refluxed for a period of 20 hours. The reaction mixture wascooled, filtered through Celite, and concentrated in vacuo. The residuewas chromatographed on silica gel using 10% ethylacetate in hexane aseluent to yield 0.74 gm (51%) of2-(p-methoxybenzoyl)-3-methyl-4-benzyloxy-7-propylbenzofuran.

¹ H NMR 0.93 (t, 3H, J=7 Hz, CH₃), 1.67 (sextet, 2H, J=7 Hz, CH₂), 2.75(s, 3H, CH₃), 2.75 (t, 2H, J=7 Hz, CH₂), 3.83 (s, 3H, CH₃), 5.13 (s, 2H,CH₂), 6.60 (d, 1H, J=9 Hz, H5), 6.93 (d, 2H, J=9 Hz, protons ortho tomethoxy), 7.10 (d, 1H, J=9 Hz, H6), 7.40 (s, 5H, phenyl protons), 8.10(d, 2H, J=9 Hz, protons meta to methoxy).

(c) Preparation of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-7-propylbenzofuran

A mixture of2-(p-methoxybenzoyl)-3-methyl-4-benzyloxy-7-propylbenzofuran (0.10 gm,0.24 mmole) in ethanol was hydrogenated in a Parr hydrogenator in thepresence of 10% palladium on charcoal at 40 psi for a period of 7 hours.The catalyst was filtered off, washed with some ethanol, and thefiltrate was concentrated in vacuo to yield2-(p-methoxybenzyl)-3-methyl-4-hydroxy-7-propylbenzofuran.

¹ H NMR 0.90 (t, 3H, J=7 Hz, CH₃), 1.63 (sextet, 2H, J=7 Hz, CH₂), 2.33(s, 3H, CH₃), 2.70 (t, 2H, J=7 Hz, CH₂), 3.73 (s, 3H, CH₃), 3.93 (s, 2H,CH₂), 4.97 (s, 1H, OH), 6.37 (d, 1H, J=9 Hz, H5), 6.78 (d, 2H, J=9 Hz,protons ortho to methoxy), (d, 1H, J=9 Hz, H6), 7.17 (d, 2H, J=9 Hz,protons meta to methoxy).

EXAMPLE 27 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (a)Preparation of 2-(p-methoxybenzoyl)-3-methyl-5-allyloxybenzofuran.

A mixture of 2-hydroxy-5-allyloxyacetophenone (7.7 gm; 40.0 mmoles),potassium carbonate (6.90 gm; 50.0 mmoles) and p-methoxyphenacyl bromide(11.4 gm, 50.0 mmoles) in acetone (100 mL) was refluxed for a period of22 hours. The reaction mixture was cooled, filtered through Celite, andconcentrated in vacuo. The residue was chromatographed on silica gelusing 50% ethylacetate in hexane as eluent to yield 7.2 gm (56%) of2-(p-methoxybenzoyl)-3-methyl-5-allyloxybenzofuran, mp. 74°-76° C.

¹ H NMR 2.60 (s, 3H, CH₃), 3.88 (s, 3H, CH₃), 4.60 (m, 2H, CH2), 5.40(m, 2H, CH₂) 6.10 (m, 1H, CH), 7.10 (m, 4H, protons ortho to methoxy, H4and H6), 7.43 (1H, J=9 Hz, H7), 8.17 (d, 2H, J=9 Hz, protons ortho tomethoxy).

(b) Preparation of2-(p-methoxybenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran

A mixture of 2-(p-methoxybenzoyl)-3-methyl-5-allyloxybenzofuran (1 gm,3.10 mmole) in ortho dichlorobenzene (5 mL) was refluxed under nitrogenfor a period of 5 hours. On cooling, the product crystallized. It wasdiluted with hexane, filtered, washed with hexane, and air-dried toyield 870 mg (87%) of2-(p-methoxybenzoyl)-3-methyl-4-allyl-5-hydroxy-benzofuran, mp.155°-158° C.

¹ H NMR 2.68 (s, 3H, CH₃), 3.80 (m, 5H, CH₃ and CH₂), 5.00 (m, 2H, CH₂),6.03 (m, 1H, CH), 6.90 (d, 3H, protons ortho to methoxy and H6), 7.23(1H, J=9 Hz, H7), 8.03 (d, 2H, J=9 Hz, protons ortho to methoxy).

(c) Preparation of2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran

A solution of 2-(p-methoxybenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran(3 gm, 9.3 mmoles) in ethanol (150 mL) was hydrogenated in a Parrhydrogenator in the presence of 10% palladium on charcoal at 40 psi fora period of 3 hours. The catalyst was filtered off, washed with someethanol, and the filtrate was concentrated in vacuo. The residue wasrecrystallized from hexane to yield (1.1 gm, 38%) of2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp. 91°-93°C.

¹ H NMR 1.00 (t, 3H, J=7 Hz, CH₃), 1.63 (sextet, 2H, J=7 Hz, CH₂), 2.33(s, 3H, CH₃), 2.87 (t, 2H, J=7 Hz, CH₂), 3.73 (s, 3H, CH₃), 3.93 (s, 2H,CH₂), 4.37 (s, 1H, OH), 6.63 (d, 1H, J=9 Hz, H6), 6.78 (d, 2H, J=9 Hz,protons ortho to methoxy), 7.07 (d, 1H, J=9 Hz, H7), 7.13 (d, 2H,protons meta to methoxy).

EXAMPLE 28 2-(p-methoxybenzyl)-3-methyl-4-hydroxybenzofuran (a)Preparation of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran

A mixture of 2,6-dihydroxyacetophenone (5.35 gm; 35.0 mmoles), potassiumcarbonate (4.83 gm; 35.0 mmoles), and p-methoxyphenacylbromide (8.05 gm;35.0 mmoles) in acetone (150 mL) was refluxed for a period of 22 hours.The reaction mixture was cooled, filtered through Celite, andconcentrated in vacuo. The residue was dissolved in methylene chlorideand washed with 1N sodium hydroxide. The aqueous phase was thenacidified with 20% citric acid. The solid was filtered, washed withwater, and air-dried to yield 6.5 gm (65%) of2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran, mp. 192°-195° C.

¹ H NMR 2.80 (s, 3H, CH₃), 3.90 (s, 3H, CH₃), 6.73 (d, 1H, J=9 Hz, H5),7.07 (m, 4H, protons ortho to methoxy, H5 and H6 ), 8.13 (d, J=9 Hz, 2H,proton ortho to carbonyl).

(b) Preparation of 2-(p-methoxybenzyl)-3-methyl-4-hydroxybenzofuran

A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran (2.0 gm;7.0 mmoles), 99% hydrazine (50 mL) and potassium hydroxide (2.7 gm; 49mmoles) in ethylene glycol (50 mL) was heated at 140° C. for a period of2.5 hours and at 195° C. for one hour. The reaction mixture was cooled,poured in water, and extracted with ethylacetate. The organic phase waswashed with 20% citric acid, with brine, dried (Na₂ SO₄), andconcentrated in vacuo. The residue was chromatographed on silica gelusing 20% ethylacetate in hexane as eluent to yield 700 gm (37%) of2-(p-methoxybenzyl)-3-methyl-4-hydroxybenzofuran, mp.130°-133° C.

¹ H NMR 2.40 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 4.00 (s, 2H, CH₂), 5.04(s, 1H, OH), 6.48 (d, 2H, J=9 Hz, H5), 6.88 (m, 4H, protons ortho tomethoxy, H6 and H7), 7.15 (d, J=9 Hz, 2H, proton meta to methoxy).

Anal. Calcd for C₁₇ H₁₆ O₃ : C, 76.09; H, 6.01; Found: C, 76.21; H,6.39.

EXAMPLE 29 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propylbenzofuran (a)Preparation of 2-(p-methoxybenzoyl)-3-methyl-4-allyloxybenzofuran

A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran (0.60 gm;2.2 mmoles), potassium carbonate (0.83 gm; 6.0 mmoles) and allyl bromide(0.73 gm; 6.0 mmoles) in acetone (25 mL) was refluxed for a period of 22hours. The reaction mixture was cooled, filtered through Celite, andconcentrated in vacuo. The residue was chromatographed on silica gelusing 15% ethylacetate in hexane as eluent to yield2-(p-methoxybenzoyl)-3-methyl-4-allyloxybenzofuran.

¹ H NMR 2.40 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 4.00 (s, 2H, CH₂),4.64 (m,2H, CH₂), 5.40 (m, 2H, ch2), 6.12 (m, 1H, CH), 6.60 (d, 1H, J=9 Hz, H5),6.84 (d, 2H, J=9 Hz, protons ortho to methoxy), 7.00 (d, 1H, J=9 Hz,H7), 7.06 (d, 1H, J=9 Hz, H6), 7.15 (d, J=9 Hz, 2H, proton meta tomethoxy).

Anal. Calcd for C₂₀ H₂₀ O₃ : C, 77.89; H, 6.53; Found: C, 77.87; H,6.76.

(b) Preparation of2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-allylbenzofuran

A solution of 2-(p-methoxybenzoyl)-3-methyl-4-allyloxybenzofuran (0.7gm; 2.2 mmoles) in orthodichlorobenzene (3 mL) was refluxed undernitrogen for a period of 4 hours. The mixture was cooled to roomtemperature and purified by chromatography on silica gel using 15%ethylacetate in hexane as eluent to yield 650 mg (93%) of2-(p-methoxyenzoyl)-3-methyl-4-hydroxy-5-allylbenzofuran, mp. 48°-50° C.

¹ H NMR 2.41 (s, 3H, CH₃), 3.44 (m, 2H, CH₂), 3.78 (s, 3H, CH₃), 4.00(s, 2H, CH₂), 5.23 (m, 2H, CH₂), 6.03 (m, 1H, CH), 6.84 (d, 2H, J=9 Hz,protons ortho to methoxy), 6.88 (s, 2H,H6 and H7), 7.15 (d, J=9Hz, 2H,proton meta to methoxy).

Anal. Calcd for C₂₀ H₂₀ O₃ : C, 77.89; H, 6.53; Found: C, 77.80; H,6.81.

(c) Preparation of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propylbenzofuran.

A solution of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-allylbenzofuran(40 mg) in ethanol (50 mL) was hydrogenated in a Parr hydrogenator inthe presence of 10% palladium on charcoal at 40 psi. The catalyst wasfiltered and the filtrate was concentrated to dryness to yield2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propylbenzofuran, identical tothe product prepared by the route described in Example 1.

EXAMPLE 30 2-benzyl-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (a)Preparation of2-benzoyl-3-methyl-4-benzoyloxy-5-propyl-7-chlorobenzofuran

A solution of benzoyl chloride (3.03 gm; 21.6 mmoles) in ethylenedichloride (20 mL) was added slowly to a cooled suspension of aluminiumchloride (5.8 gm; 43 mmoles) in ethylenedichloride (100 mL).

After stirring for a period of 10 minutes,3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1.62 gm; 7.2 mmoles) indichloroethylene (20 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 1 hour. It wascooled with an ice-bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the aqueous phasewas extracted with methylene chloride. The orqanic phases were combined,dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 10% ethylacetate in hexaneto yield 1.18 gm (63%) of2-benzoyl-3-methyl-4-benzoyloxy-5-propyl-7-chlorobenzofuran, mp.141°-142° C.

¹ H NMR 0.93 (t, J=7 Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.55(s, 3H, CH₃), 2.60 (t, J=7 Hz, 2H, CH₂), 7.33 (s, 1H. H6), 7.50 (m, 6H,meta and para protons of benzoyl group), 8.20 (m, 4H, protons ortho tocarbonyl).

Anal. Calcd for C₂₆ H₂₁ ClO₄ : C, 72.13; H, 4.88; Cl, 8.18. Found: C,71.30; H, 5.05; Cl, 8.37.

(b) Preparation of2-benzyl-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

To an ice-cold suspension of aluminium chloride (2.50 gm, 18 mmoles) inether (300 mL) was added slowly lithium aluminium hydride (3.0 gm, 80mmoles). After stirring for a period of 10 minutes,2-benzyl-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (2.31 gm, 5.33mmoles) in ether (10 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 10 minutes. It wascooled with an ice bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the aqueous phasewas extracted with ether. The organic phases were combined, washed withbrine, dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 10% ethylacetate in hexaneto yield 1.30 gm (77%) of2-benzyl-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp. 69°-70° C.

¹ H NMR 0.98 (t, J=7 Hz, 3H, CH₃), 1.60 (sextet, J=7 Hz, 2H, CH₂), 2.40(s, 3H, CH₃), 2.63 (t, J=7 Hz, 2H, CH₂), 4.00 (s, 2H, CH₂), 4.80 (s, 1H,OH), 6.90 (s, 1H, H6), 7.23 (s, 5H, phenyl protons).

Anal. Calcd for C₁₉ H₁₉ ClO₂ : C, 72.49; H, 6.08; Cl, 11.26. Found: C,72.48; H, 6.16; Cl, 11.02.

EXAMPLE 312-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

To a solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (100mg, 0.29 mmole) in methylene chloride (5 mL) cooled to -78° C., wasadded dropwise over a period of 5 minutes a lM solution of borontribromide (0.3mL; 0.3 mmole) in methylene chloride. The temperature wasallowed to rise to room temperature and the reaction mixture was stirredfor 3 hours. It was then cooled to -78° C. and methanol (2 mL) was addedrapidly. The resulting solution was poured into water. The phases wereseparated and the aqueous phase was extracted with methylene chloride.The organic phases were combined, washed with brine, dried (Na₂ SO₄),and concentrated in vacuo. The residue was chromatographed on silica geland eluted with 15% ethyl acetate in hexane to yield 63 mg gm (66%) of2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp.142°-143° C.

EXAMPLE 322-(p-bromobenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (a)Preparation of2-(p-bromobenzoyl)-3-methyl-4-(p-bromobenzoyloxy)-5-propyl-7-chlorobenzofuran

A solution of p-bromobenzoyl chloride (1.1 gm; 5.0 mmoles) in ethylenedichloride (5 mL) was added slowly to a cooled suspension of aluminiumchloride (3.3 gm; 25 mmoles) in ethylene dichloride (75 mL). Afterstirring for a period of 10 minutes,3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.95 gm; 4.2 mmoles) indichloroethylene (20 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 1 hour. It wascooled with an ice-bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the aqueous phasewas extracted with methylene chloride. The organic phases were combined,dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 10% ethylacetate in hexaneto yield 260 mg gm of2-(p-bromobenzoyl-3-methyl-4-(p-bromobenzoyloxy)-5-propyl-7-chlorobenzofuran.

¹ H NMR 0.97 (t, J=7 Hz, 3H, CH₃), 1.70 (sextet, J=7 Hz, 2H, CH₂), 2.60(s, 3H, CH₃), 2.63 (t, J=7 Hz, 2H, CH₂), 7.43 (s, 1H. H6), 7.80 (m, 4H,protons meta to carbonyl), 8.20 (m, 4H, protons ortho to carbonyl).

(b) Preparation of2-(p-bromobenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

To an ice-cold suspension of aluminium chloride (0.5 gm, 3.6 mmoles) inether (100 mL) was added slowly lithium aluminium hydride (1.0 gm, 26.7mmoles). After stirring for a period of 10 minutes,2-(p-bromobenzyl)-3-methyl-4-(p-bromobenzoyloxy-5-propyl-7chlorobenzofuran (0.22 gm, 0.37 mmole) in ether (10 mL) was added over aperiod of 2 minutes. The reaction mixture was stirred at roomtemperature for 10 minutes. It was cooled with an ice-bath and ice wasadded slowly. When the vigorous reaction subsided, the organic layer wasseparated and the aqueous phase was extracted with ether. The organicphases were combined, washed with brine, dried (Na₂ SO₄), andconcentrated in vacuo. The residue was chromatographed on silica gel andeluted with 10% ethyl acetate in hexane to yield 178 mg (97%) of2-benzyl-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran.

¹ H NMR 0.98 (t, J=7 Hz, 3H, CH₃), 1.57 (sextet, J=7 Hz, 2H, CH₂), 2.33(s, 3H, CH₃), 2.53 (t, J=7 Hz, 2H, CH₂), 3.98 (s, 2H, CH₂), 4.80 (s, 1H,OH), 6.93 (s, 1H, H6), 7.10 (d, 2H, J=9 Hz, protons ortho to bromo),7.33 (d, 2H,J=9 Hz, protons meta to bromo).

EXAMPLE 332-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran(a) Preparation of2-(p-methoxyphenacetyl)-3-methyl-4-(p-methoxyphenacetyl-oxy)-5-propyl-7-chlorobenzofuran

A solution of p-methoxyphenacetyl chloride (2.0 gm; 11 mmoles) inethylene dichloride (5 mL) was added slowly to a cooled suspension ofaluminium chloride (2.9 gm; 22 mmoles) in ethylene dichloride (145 mL).After stirring for a period of 10 minutes,3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.87 gm; 3.6 mmoles) indichloroethylene (20 mL) was added over a period of 2 minutes. Thereaction mixture was stirred at room temperature for 1 hour. It wascooled with an ice-bath and ice was added slowly. When the vigorousreaction subsided, the organic layer was separated and the aqueous phasewas extracted with methylene chloride. The organic phases were combined,dried (Na₂ SO₄), and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 15% ethylacetate intoluene to yield 1.3 gm of2-(p-methoxyphenacetyl)-3-methyl-4-(p-methoxyphenac-etyloxy)-5-propyl-7-chlorobenzofuran.

¹ H NMR 0.83 (t, J=7 Hz, 3H, CH₃), 1.50 (sextet, J=7 Hz, 2H, CH₂), 2.40(s, 3H, CH₃), 2.40 (t, J=7 Hz, 2H, CH₂), 3.80 (m, 10H, CH₃ and CH₂),6.80 (m, 4H, protons ortho to methoxy), 7.2 (m, 5H, H6 and protons metato methoxy).

(b) Preparation of2-(p-methoxyphenethyl)-3-methyl-4-(p-methoxyphenacetyloxy)-5-propyl-7-chlorobenzofuran(0.76 gm, 1.4 mmoles) in tetrahydrofuran (25 mL) was added a solution of1M diborane in tetrahydrofuran (5 mL; 5 mmoles). The reaction wasstirred at room temperature for 30 minutes. Methanol was then added andthe volatiles were removed in vacuo to yield a residue that was taken upin tetrahydrofuran (25 mL) and added to a mixture of aluminium chloride(0.67 gm, 4 mmoles) and lithium aluminium hydride (0.80 gm, 21 mmoles)in tetrahydrofuran (25 mL). The mixture was stirred at room temperaturefor 2 hours and was refluxed for 15 minutes. It was cooled with anice-bath and ice was added slowly. When the vigorous reaction subsided,the organic layer was separated and the aqueous phase was extracted withether. The organic phases were combined, washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was chromatographed onsilica gel and eluted with 15% ethyl acetate in hexane to yield 100 mg(20%) of2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran.

¹ H NMR 0.98 (t, J=7 Hz, 3H, CH₃), 1.63 (sextet, J=7 Hz, 2H, CH₂), 2.17(s, 3H, CH₃), 2.58 (t, J=7 Hz, 2H, CH₂), 2.98 (s, 4H, CH₂), 3.80 (s, 2H,CH₂), 4.80 (s, 1H, OH), 6.80 (d, 2H, J=9 Hz, protons ortho to methoxy),6.88 (s, 1H, H6), 7.03 (d, 2H,J=9 Hz, protons meta to methoxy).

EXAMPLE 34 2-(p-methoxyphenethyl)-3-methyl-4-hydroxybenzofuran (a)Preparation of 3-methyl-4-acetoxybenzofuran

A solution of 3-methyl-4-hydroxybenzofuran (5.0 gm, 34.7 mmoles), aceticanhydride (50 mL) and triethylamine (25 mL) in tetrahydrofuran (150 mL)was stirred at room temperature overnight. The volatiles were removed invacuo and the residue was purified by chromatography on silica gel.Elution with 15% ethylacetate in hexane yielded3-methyl-4-acetoxybenzofuran.

¹ H NMR 2.17 (s, 3H, CH₃), 2.40 (s, 3H, CH₃), 6.88 (d of d, 1H, H5),7.20 (m, 3H, H2, H6 and H7).

(b) Preparation of2-E-(1-(p-methoxyphenyl)-vinyl)-3-methyl-4-acetoxybenzofuran

A mixture of 3-methyl-4-acetoxybenzofuran (3.7 gm, 19.4 mmoles),palladium (II) acetate (5.6 gm, 25 mmoles), and p-methoxystyrene (6.7gm, 50 mmoles) in acetic acid (100 mL) was refluxed for 45 minutes. Themixture was filtered through Celite and the filtrate was concentrated invacuo. The residue was slurried with hexane, the insolubles weredecanted, and the hexane solution was left to crystallize. The solid wasfiltered, washed with hexane and air dried to yield 1.6 gm (26%)2-E-(1-(p-methoxyphenyl)-vinyl)-3-methyl-4-acetoxybenzofuran, mp.146°-148° C.

¹ H NMR 2.30 (s, 3H, CH₃), 2.33 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 7.10(m, 9H, aromatic protons and vinyl protons)

(c) Preparation of 2-(p-methoxyphenethyl)-3-methyl-4-acetoxybenzofuran

A solution of2-E-(1-(p-methoxyphenyl)-vinyl)-3-methyl-4-acetoxybenzofuran (1.29 gm, 4mmoles) in ethanol (75 mL) was hydrogenated in a Parr hydrogenator inthe presence of 5% palladium on charcoal at 50 psi for a period of 2hours. The catalyst was filtered off and the filtrate was concentratedin vacuo to yield 1.26 gm (98%) of2-(p-methoxyphenethyl)-3-methyl-4-acetoxybenzofuran, mp. 66°-69° C.

¹ H NMR 2.10 (s, 3H, CH₃), 2.37 (s, 3H, CH₃), 2.97 (s, 1H, CH₂), 3.80(s, 3H, CH₃), 7.10 (m, 7H, aromatic protons).

(d) Preparation of 2-(p-methoxyphenethyl)-3-methyl-4-hydroxybenzofuran

A solution of 2-(p-methoxyphenethyl)-3-methyl-4-acetoxy-benzofuran (1gm, 3 mmoles) in methanol (50 mL) and 1N sodium hydroxide (10 mL) wasstirred at room temperature for a period of 10 minutes. The mixture wasacidified with 20% citric acid and the volatiles were removed in vacuo.The aqueous residue was extracted with ether, washed with water, dried(Na₂ SO₄), filtered, and concentrated to yield a residue that waschromatographed on silica gel. Elution with 15% ethylacetate in hexaneyielded 2-(p-methoxyphenethyl)-3-methyl-4-hydroxybenzofuran, mp. 72°-75°C.

¹ H NMR 2.20 (s, 3H, CH₃), 2.97 (s, 4H, CH₂), 3.80 (s, 3H, CH₃), 6.90(m, 7H, aromatic protons).

EXAMPLE 35 2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-propylbenzofuran(a) Preparation of 2-(p-methoxyphenethyl)-3-methyl-4-allyloxybenzofuran

A mixture of 2-(p-methoxyphenethyl)-3-methyl-4-hydroxybenzofuran (1.3gm; 4.6 mmoles), potassium carbonate (1.38 gm, 10 mmoles), and allylbromide (1.2 gm, 10 mmoles) in acetone (50 mL) was refluxed for a periodof 5 hours. The solids were filtered off and the filtrate wasconcentrated in vacuo. The residue was chromatographed on silica gel andeluted with 15% ethylacetate in hexane to yield 0.9 gm of2-(p-methoxyphenethyl)-3-methyl-4-allyloxybenzofuran, which was used assuch for the next step.

(b) Preparation of2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-allylbenzofuran

A solution of 2-(p-methoxyphenethyl)-3-methyl-4-allyloxybenzofuran (0.9gm, 2.8 mmoles) in ortho dichlorobenzene (15 mL) was refluxed for 4.5hours under a nitrogen atmosphere. The mixture was cooled to roomtemperature and was chromatographed on silica gel. Elution with 15%ethylacetate in hexane yielded 0.6 gm (67%) of2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-allylbenzofuran.

¹ H NMR 2.10 (s, 3H, CH₃), 2.93 (s, 4H, CH₂), 3.40 (m, 2H, CH₂), 3.73(s, 3H, CH₃), 5.17 (m, 2H, CH₂), 6.00 (m, 1H, CH), 6.73 (d, 2H, J=9 Hz,protons ortho to methoxy), 6.87 (s, 2H, H6 and H7), 7.08 (d, 2H, protonsmeta to methoxy).

(c) Preparation of2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-propylbenzofuran

A solution of2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-allylbenzofuran (0.65 gm, 2mmoles) in ethanol (50 mL) was hydrogenated in a Parr hydrogenator inthe presence of 5% palladium on charcoal at 50 psi for a period of 2hours. The catalyst was filtered off and the filtrate was concentratedin vacuo to yield2-(p-methoxyphenethyl)-3-methyl-4-hydroxy-5-propylbenzofuran, mp 77°-79°C.

¹ H NMR 0.93 (t, 3H J=7 Hz, CH₃), 1.60 (sextet, 2H, J=7 Hz, CH₂), 2.17(s, 3H, CH₃), 2.57 (t, 2H, J=7 Hz, CH₂), 2.90 (s, 4H, CH₂), 3.73 (s, 3H,CH₃), 4.80 (s, 1H, OH), 6.73 (d, 2H, J=9 Hz, protons ortho to methoxy),6.87 (s, 2H, H6 and H7), 7.03 (d, 2H, protons meta to methoxy).

EXAMPLE 36 2-Benzyl-3-methyl-4,5-dihydroxybenzofuran (a) Preparation of3-(3,4-methylenedioxyphenoxy)-4-phenyl-2-butanone

A mixture of sesamol (3,4-methylenedioxyphenol) (0.69 gm, 5 mmoles),1-chloro-1-acetyl-2-phenethyl-1-triphenylphosphonium chloride (2.4 gm, 5mmoles), and potassium carbonate (2.76 gm; 20 mmoles) inmethylethylketone (50 mL) was refluxed for a period of 3 hours. Morephosphonium salt was then added (0.4 gm, 0.84 mmoles) and reflux wascontinued for another 3 hours.The reaction mixture was cooled, filteredthrough Celite and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 20% ethylacetate in hexaneto yield 629 mg (46%) of3-(3,4-methylenedioxyphenoxy)-4-phenyl-2-butanone as an oil.

¹ H NMR 2.10 (s, 3H, CH₃), 3.10 (d, 2H,J=7 Hz, CH₂), 4.63 (t, 1H, J=7Hz, CH), 5.90 (s, 2H, CH₂), 6.2 (d of d, 1H, J=9 Hz, 3 Hz, HH6), 6.43(d, 1H, J=3 Hz, H2), 6.67 (d, 1H, J=9 Hz, H5).

Anal Calcd. for C₁₇ H₁₆ O₄ : C, 71.86; H, 5.67. Found: C, 71.92; H,5.88.

(b) Preparation of 2-benzyl-3-methyl-5,6-methylenedioxybenzofuran

A mixture of 3-(3,4-methylenedioxyphenoxy)-4-phenyl-2-butanone (0.70 gm,2.45 mmoles) in polyphosphoric acid (3.5 gm) was stirred by hand untilthe initial exothermic reaction subsided. The mixture was stirred inice/water and the solid was collected, washed with water, and dried invacuo. The solid was chromatographed on silica gel and eluted with 20%ethylacetate in hexane to yield 479 mg (73%) of2-benzyl-3-methyl-5,6-methylenedioxybenzofuran.

Anal. Calcd. for C₁₇ H₁₄ O₃ : C, 76.68; H, 5.30. Found: C, 76.55; H,5.24.

(c) Preparation of 2-benzyl-3-methyl-5,6-dihydroxybenzofuran

A solution of 2-benzyl-3-methyl-5,6-methylenedioxybenzofuran (226 mg,0.85 mmole) in methylene chloride (10 mL) was cooled at -65° C. and a 1Msolution of boron tribromide in methylene chloride (0.85 mL) was addeddropwise. The mixture was allowed to warm up to -25° C. and was kept inthat range for 1 hour. Methanol (5 mL) was then added and the mixturewas evaporated in vacuo. The residue was chromatographed on silica geland eluted with 25% ethylacetate in hexane to yield 128 mg of2-benzyl-3-methyl-5,6-dihydroxybenzofuran, mp. 95.5°-98° C.

¹ H NMR 2.15 (s, 3H, CH₃), 4.03 (s, 2H, CH₂), 6.88 (s, 1H, H4), 6.95 (s,1H, H7), 7.23 (m, 5H, phenyl).

EXAMPLE 372-(p-carboxymethoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran(a) Preparation of2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran

A solution of2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1gm; 3 mmoles) in pyridine (15 mL) and acetic anhydride (3 mL) wasstirred at 50° C. for 15 minutes. The volatiles were removed in vacuoleaving a residue that crystallised on cooling. It was slurried withhexane, filtered, washed with hexane, and air dried to yield 1.1 gm(87%) of2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran, mp.119°-120° C.

¹ NMR 0.93 (t, 3H, J=7 Hz, CH₃), 1.60 (sextet, 2H, J=7 Hz, CH₂), 2.20(s, 3H, CH₃), 2.27 (s, 3H, CH₃), 2.33 (s, 3H, CH₃), 2.37 (t, 2H, J=7 Hz,CH₂), 4.00 (s, 2H, CH₂), 7.00 (d, 2H, J=9 Hz, protons ortho to methoxy),7.07 (s, 1H, H6), 7.20 (d, 2H, J=9 Hz, protons meta to methoxy).

(b) Preparation of2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran

A solution of2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (150mg, 0.36 mmole) in methanol (5 mL) and a saturated solution of ootassiumcarbonate (3 mL) was stirred at room temperature for 5 minutes. Thereaction was poured in water, extracted with methylene chloride, washedwith brine, dried (Na₂ SO₄), and concentrated in vacuo to yield 107 mg(79%) of2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran.

¹ NMR: 0.93 (t, 3H, J=7 Hz, CH₃), 1.60 (sextet, 2H, J=7 Hz, CH₂), 2.18(s, 3H, CH₃), 2.37 (s, 3H, CH₃), 2 50 (t, 2H, J=7 Hz, CH₂), 3.97 (s, 2H,CH₂), 5.20 (s, 1H, OH), 6.67 (d, 2H, J=9 Hz, protons ortho to methoxy),7.03 (s, 1H, H6), 7.07 (d, 2H, J=9 Hz, protons meta to methoxy).

(c) Preparation of2-(p-carboethoxymethoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran

A mixture of2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (107mg; 0.28 mmole), ethylbromoacetate (100 mg, 0.60 mmole), potassiumcarbonate (100 mg, 0.73 mmole) in acetone (10 mL) was refluxed for 30minutes. The solids were filtered off, the filtrate was concentrated invacuo to yield a residue that was purified by chromatography on silicagel. Elution with 20% ethylacetate in hexane yielded 133 (100%) of2-(p-carboethoxymethoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran.

¹ NMR: 0.93 (t, 3H, J=7 Hz, CH₃), 1.33 (t, 3H, J=7 Hz, CH₃), 1.60(sextet, 2H, J=7 Hz, CH₂), 2.18 (s, 3H, CH₃), 2.37 (s, 3H, CH₃), 2.50(t, 2H, J=7 Hz, CH₂), 4.00 (s, 2H, CH₂), 4.23 (q, 2H, J=7 Hz, CH₂), 4.53(s, 2H, CH₂), 6.83 (d, 2H, J=9 Hz, protons ortho to methoxy), 7.10 (s,1H, H6), 7.23 (d, 2H, J=9 Hz, protons meta to methoxy).

(e) Preparation of2-(p-carboxymethoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

A solution of2-(p-carboethoxymethoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran(133 mg; 0.28 mmole) in methanol (10 mL) and 10N sodium hydroxide (1 mL)was stirred at room temperature for a period of 30 minutes. Water wasthen added and the mixture was acidified with 6N hydrochloric acid. Thesolid was filtered, washed with water, and air-dried to yield 93 mg(82%) of2-(p-carboxymethoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran,mp. 179°-180° C.

¹ NMR 1.00 (t, 3H, J=7 Hz, CH₃), 1.67 (sextet, 2H, J=7 Hz, CH₂), 2.43(s, 3H, CH₃), 2.67 (s, 3H, CH₃), 4.00 (s, 2H, CH₂), 4.60 (s, 2H, CH₂),6.87 (d, 2H, J =9 Hz, protons ortho to methoxy), 6.93 (s, 1H, H6), 7.20(d, 2H, J=9 Hz, protons meta to methoxy).

EXAMPLE 382-(p-methoxybenzyl)-3-methyl-4-succinyloxy-5-propyl-7-chlorobenzofuran

A solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.5gm, 1.45 mmole), 0.58 succinic anhydride (0.58 gm, 5.8 mmoles), andtriethylamine (0.58 gm, 5.8 mmoles) in tetrahydrofuran (15 mL) wasrefluxed overnight. The volatiles were removed in vacuo and the residuewas purified by chromatography on silica gel. Elution with 15%ethylacetate in hexane containing also 5% acetic acid yielded 0.45 gm(69%) of2-(p-methoxybenzyl)-3-methyl-4-succinyloxy-5-propyl-7-chlorobenzofuran,mp. 151°-152° C.

¹ NMR: 10.93(t, 3H, J=7 Hz, CH₃), 1.60 (sextet, 2H, J=7 Hz, CH₂), 2.27(s, 3H, CH₃), 2.57 (s, 3H, CH₃), 2.90 (m, 4H, CH₂), 3.80 (s, 3H, CH₃),4.00 (s, 2H, CH₂), 6.83 (d, 2H, J=9 Hz, protons ortho to methoxy), 7.07(s, 1H, H6), 7.20 (d, 2H, J=9 Hz, protons meta to methoxy).

EXAMPLE 392-(p-carboethoxymethoxybenzyl)-3-methyl-4-carboethoxymethoxy-5-propyl-7-chlorobenzofuran

A mixture of2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (483mg; 1.46 mmole), ethylbromoacetate (325 mg, 1.90 mmole), and potassiumcarbonate (500 mg, 3.62 mmoles) in acetone (20 mL) was refluxed for 60minutes. The solids were filtered off. The filtrate was concentrated invacuo to yield a residue that was purified by chromatography on silicagel. Elution with 20% ethylacetate in hexane yielded 520 (85%) of2-(p-carboethoxymethoxybenzyl)-3-methyl-4-carboethoxymethoxy-5-propyl-7-chlorobenzofuran.

¹ NMR: 0.93 (t, 3H, J=7 Hz, CH₃), 0.98 (t, 3H, J=7 Hz, CH₃), 1.33 (t,3H, J=7 Hz, CH₃), 1.60 (sextet, 4H, J=7 Hz, CH₂), 2.33 (t, 4H, J=7 Hz,CH₂), 4.00 (q, 2H, J=7 Hz, CH₂), 4.18 (s, 2H, CH₂), 4.30 (s, 2H, CH₂),6.57 (d, 2H, J=9 Hz, protons ortho to methoxy), 6.67 (s, 1H, H6), 6.90(d, 2H, J=9 Hz, protons meta to methoxy).

EXAMPLE 40 O-sulfate of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran,ammonium salt

A solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (5gm, 14.5 mmoles) was added at 0° C. to a mixture of diethyl aniline (4.3ml) and chlorosulfonic acid (1 ml) in carbon disulfide (50 ml). Thetemperature was allowed to rise to room temperature and after 15minutes, it was refluxed for 15 minutes. The reaction mixture wasevaporated to dryness and the residue was purified by preparative thinlayer chromatography. Eluting with a mixture of methanol, chloroform andammonium hydroxide in the ratio of 4:8:1 (v/v/) yielded 5 gm of thesulfate ester of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran asits ammonium salt; m.p.: 207°-209° C.

¹ NMR 0.93 (t, 3H, J=7 Hz, CH₃), 1.70 (sextet, 2H, J=7 Hz, CH₂), 2.47(s, 3H, CH₃, 2.97 (t, J=7 Hz, 2H, CH₂), 3.70 (s, 3H, CH₃), 4.03 (s, 2H,CH₂), 6.83 (d, 2H, J=9 Hz, protons ortho to methoxy), 7.10 (d, 2H, J=9Hz, protons meta to methoxy), 7.27 (s, 1H, H6).

EXAMPLE 41 O-phosphate of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran

A solution of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (5gm, 14.5 mmoles) in chloroform (25 ml) was added at 0° C. to a solutionof phosphorus oxychloride (75 ml) in pyridine (25 ml) and acetone (250ml). The mixture was stirred at room temperature for a period of 1 hourand refluxed for 2 hours. The reaction mixture was evaporated to drynessand the residue was slurried in a small volume of water. The solids werefiltered, washed, and air-dried to yield the phosphate ester of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran.

¹ NMR: 0.93 (t, 3H, J-7 Hz, CH₃), 1.60 (sextet, 2H, J=7 Hz, CH₂), 2.27(s, 3H, CH₃), 2.87 (t, J=7 Hz, 2H, CH₂), 3.80 (s, 3H, CH₃), 4.00 (s, 2H,CH₂), 6.83 (d, 2H, J=9 Hz, protons ortho to methoxy), 7.10 (d, 2H, J=9Hz, protons meta to methoxy), 7.15 (s, 1H, H6).

Anal. Calcd. C, 56.54; H, 5.18; Cl, 8.35; P, 7.30. Found: C, 56.59; H,5.21; Cl, 8.52; P, 7.43. ##STR18##

An alternative preparation of compounds of structure I is shown inScheme V, which is an improved modification of Scheme I. Reaction ofsubstituted acyl phenols (IIa) with various substituted phenacylbromides (IIIa) in the presence of 0.5 molar equivalents of cesiumcarbonate in acetonitrile at room temperatures gave the monoalkylatedproducts (XII). Products (XII) can be isolated but in most cases theyare cyclized in situ to the benzofuran (IVa) by the addition of aqueousHCl and reflux for 6-8 hours. It is important to note that in the casewhere Y=Y¹ =hydrogen or alkyl, alkylation followed by cyclization can beeffected by simply refluxing (IIa) and (IIIa) with potassium carbonatein acetone. In the case where Y¹ =halogen and Y=alkyl, using other baseslike potassium carbonate or sodium hydride or even a slight excess ofCsCO₃, the reaction takes an alternative path to give only the7-membered ring derivatives (XIII).

In general the reduction of the benzoyl ketone (IVa) to thecorresponding benzyl derivative (Va) by lithium aluminum hydride andaluminum chloride complex can be achieved in reasonable yield. Analternative, less hazardous method using sodium cyanoborohydride in thepresence of zinc iodide gives rise to product yields of greater than 90%yield for most cases.

In the following discussion, the Arabic numbers refer to compounds inTable 1. ##STR19##

Allylation of (92) (Scheme VI) followed by Claisen rearrangement andhydrogenation gives the 5-propyl derivative (17). Chlorination of (92)gives the dichlorinated product (173). Treatment of (17) with 3eqivalents of Eschenmoser's salt (dimethylmethyleneimmonium iodide) indichloromethane gives the corresponding 7-(dimethylaminomethyl)derivative (176). This compound is reduced by NaBH₄ in refluxing ethanolto give the 5-propyl-7-methyl-derivative (94). ##STR20##

Reaction of the 3-chloro-5-t-butyl-2,6-dihydroxyacetophenone (SchemeVII) with 4-methoxyphenacyl bromide as described in Scheme V gives thedesired 5-t-butyl-4-hydroxy-7-chlorobenzofuran derivative (165) afterreduction. The t-butyl substituent is then removed by treating (165)with aluminum chloride in benzene for 1 hour. Allylation of (164)followed by Claisen rearrangement gives the 5-allyl derivative (179)which after silylation of the phenol is hydroborated to give thecorresponding alcohol (XV). Oxidation of the alcohol with Jones reagentgives the corresponding acid. Deprotection with tetra-n-butylammoniumfluoride gives the desired alcohol (180) and acid (181). Reaction of(164) with Eschenmoser's salt gives the 5-dimethylaminomethyl derivative(177) which is reduced to the 5-methyl derivative (178) with sodiumborohydride in ethanol. Quaternization of the tertiary amine with ethylbromide followed by displacement of the quaternary salt with ethanolgives the 5-(ethoxymethyl) derivative (182). ##STR21##

To prepare 166 (Scheme VIII),1-formyl-3-chloro-5-propyl-2,6-dihydroxybenzene (IIc) is prepared fromits acetophenone analog IIb. Deacylation of the latter with HBr inacetic acid gives the corresponding dihydroxybenzene derivative XIV.Formylation of the latter with hexamine in trifluroacetic acid gives IIcin 85% yield. Condensation of the latter with p-methoxyphenacyl bromideis achieved with potassium carbonate in refluxing acetone to give thecorresponding benzofuran (166) in 79% yield after reduction. Thecorresponding acetyl analog under the same conditions gives the7-membered ring product XIII as described in Scheme V.

The 3-propyl analog (167) is prepared by the standard method describedin Scheme V. The 4'-H (108), 4'-Chloro (174), 2',4'-dimethoxy (175)derivatives are also prepared as described in Scheme V. ##STR22##

To prepare the 2-phenyl analog (172) (Scheme IX),1-acetyl-3-chloro-5-propyl-2,6-dihydroxybenzene (IIb) is coupled withmethyl 2-hydroxy-2-phenylacetate in the presence ofdiethyldiazodicarboxylate and triphenylphosphine to give the coupledproduct XVII. Hydrolysis of the latter followed by cyclization in aceticanhydride and sodium acetate gives the 2-phenybenzofuran XIX which afterhydrolysis of the acetate gives compound 172. ##STR23##

To prepare the benzothiophene analog (Vb), the dihydroxyacetophenonederivative IIf (Scheme X) is reacted with dimethylthiocarbamoyl chlorideto give the corresponding O-dimethylthiocarbamate XX. Thermalrearrangement in refluxing O-dichlorobenzene of the acetate XXI of thelatter gives the S-dimethylthiocarbamate XXII which after treatment withboron tribromide gives the mercapto compound IIg. Transformation of thelatter to the benzothiophene Vb is essentially the same as thatdescribed in Scheme V.

                  TABLE 5                                                         ______________________________________                                        COMPOUNDS OF FORMULA I                                                                   Ex.                                                                Compound   No.    Scheme     mp °C.                                                                       Formula                                    ______________________________________                                        163               II         49-50 C.sub.12 H.sub.13 O.sub.2 Cl               164        44     VII        159   C.sub.17 H.sub.15 ClO.sub.3                165        43     VII        128   C.sub.21 H.sub.23 ClO.sub.3                166        51     V          88    C.sub.19 H.sub.19 ClO.sub.3                167               V          90    C.sub.22 H.sub.25 ClO.sub.3                168               V          93    C.sub.21 H.sub.23 ClO.sub.3                169               V          oil   C.sub.19 H.sub.28 O.sub.2                  170               V          104   C.sub.21 H.sub.24 O.sub.4                  171        53     X          80    C.sub.20 H.sub.21 SO.sub.2 Cl              172        52     IX         103   C.sub.18 H.sub.17 ClO.sub.2                173               VI         121   C.sub.17 H.sub.14 Cl.sub.2 O.sub.3         174               V          76    C.sub.19 H.sub.18 Cl.sub.2 O.sub.2         175               V          108   C.sub.21 H.sub.23 O.sub.4 Cl               176        21     VI         oil   C.sub.20 H.sub.22 ClNO.sub.3               177        45     VII        oil   C.sub.20 H.sub.22 ClNO.sub.3               178        46     VII        128   C.sub.18 H.sub.17 ClO.sub.3                179        48     VII        90    C.sub.20 H.sub.19 ClO.sub.3                180        49     VII        133   C.sub.20 H.sub.21 ClO.sub.4                181        50     VII        149   C.sub.20 H.sub.19 ClO.sub.5                182        47     VII        oil   C.sub.26 H.sub.21 O.sub.4 Cl               ______________________________________                                    

EXAMPLE 42 Alternate preparation of2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran(Example 23) (a) Preparation of4-hydroxy-7-chloro-2-(p-methoxybenzoyl)-3-methyl-5-propylbenzofuran

To a solution of 5-chloro-2,6-dihydroxy-3-propylacetophenone (Example23, Step a) (3.5 g, 14.5 mmol) in acetonitrile (40 mL) was added cesiumcarbonate (2.49 g, 7.65 mmol). The mixture was refluxed with stirringfor 30 min. The resulting dark red mixture was cooled to 5° C. and to itwas added a solution of 2-bromo-4'-methoxyacetophenone (3.5 g, 15.3mmol) in acetonitrile (8.0 mL). The mixture was then warmed to roomtemperature for 2 h. HCl (6N, 30 mL) was added to the reaction mixturewhich was then refluxed for another 2 h. The mixture was cooled to 0°C., diluted with ice water (30 mL) and filtered. The product was washedwith more water and dried to give the title compound.

¹ H NMR (250 MHz, CDCl₃) δ 0.95 (t, 3H), 1.6 (m, 2H), 2.5 (t, 2H), 2.75(s, 3H), 3.85 (S, 3H), 6.95 (d, 2H, J=6 Hz), 7.1 (S, 1H), 8.15 (d, 2H,J=6 Hz).

(b) Preparation of4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methyl-5-propylbenzofuran

To a stirring solution of4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methyl-5-propylbenzofuran(Step a) (27 g, 75.4 mmol) in dichloroethane (350 mL) was added zinciodide (36.85 g, 113 mmol) followed by sodium cyanoborohydride (35.54 g,565 mmol). The resulting mixture was refluxed for 6 h. The cooledmixture was poured into a cold saturated solution of ammonium chlorideacidified with HCl and stirred for 1/2 h. Extraction with ethyl acetateand chromatography (15% EtOAc in hexane) of the crude concentratedextract gave the title compound, identical with material prepared inExample 23.

Compounds 167-170 and 174 and 175 in Table 5 were prepared by themethodology of Example 42.

EXAMPLE 43 Preparation of4-hydroxy-7-chloro-5-tbutyl-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(165) (a) Preparation of 3-chloro-2,6-dihydroxyacetophenone

To 2,6-dihydroxyacetophenone (15.2 g, 160 mmol) dissolved indichloromethane (800 ml) was added N-chlorosuccinimide (14.68 g, 110mmol). The resulting solution was stirred overnight at room temperature.The reaction mixture was poured onto a flash chromatography column andeluted with dichloromethane to give the title compound.

¹ H NMR (90 MHz, CDCl₃) δ 2.72 (s, 3H) 6.45 (d, 2H, J =9 Hz) 7.32 (d,2H, J=9 Hz).

(b) Preparation of 5-chloro-2,6-dihydroxy-3-tertbutylacetophenone

To 3-chloro-2,6-dihydroxyacetophenone (from Step a, 30 g, 161 mmol)dissolved in 2-chloro-2-methylpropane (200 ml) was added H₂ SO₄ 98% (3ml). The mixture was refluxed for 4 hours, cooled and washed with H₂ O(200 ml). The organic solution was separated evaporated and the residuechromatographed on silica gel (eluted with 15% EtOAC in hexane) to givethe title compound.

¹ H NMR (90 MHz, CDCl₃) δ 1.35 (s, 9H) 2.75 (s, 3H) 7.38 (s, 1H).

(c) Preparation of4-hydroxy-7-chloro-5-t-butyl-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(165)

The title compound was prepared according to the methodology of Example42 using the starting material from Step b above.

¹ H NMR (90 MHz CDCl₃) δ 1.40 (s, 9H) 2.40 (s, 3H) 3.75 (s, 3H) 3.95 (s,2H) 5.15 (s, 1H) 6.8 (d, 2H, J =9 Hz) 7.18 (d, 3H).

EXAMPLE 44 Preparation of4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran (164)

To a cold solution (0° C.) of4-hydroxy-7-chloro-5-t-butyl-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(165)(Example 43) (10 g, 27.8 mmol) in 500 mL dichloromethane was added 5 mLof anisole followed by aluminum chloride (13 g, 0.1 mol) in portions.The mixture was allowed to stir for 1 h and then poured onto ice. Themixture was extracted with dichloromethane, the organic extracts weredried, concentrated and chromatographed to give the title compound.

¹ H NMR (250 MHz, CDCl₃) δ 6 2.38 (S, 3H), 3.85 (s, 3H), 4.1 (S, 2H),6.45 (d, 1H, J=6 Hz), 6.8 (d, 2H, J=6 Hz), 6.95 (d, 1H, J=6 Hz), 7.15(d, 2H, J=6 Hz).

Anal. Calcd. for C₁₇ H₁₅ ClO₃ : C, 67.44; H, 4.95; Cl, 11.72. Found: C,67.81; H, 5.31; Cl, 11.43.

EXAMPLE 45 Preparation of4-hydroxy-5-dimethylaminomethyl-2-(4'-methoxyphenylmethyl)-3-methyl-benzofuranhydrochloride (177)

To a solution of (164) (Example 44) (1 g, 3.3 mmol) in 25 mLdichloromethane was added Eschenmoser's salt (0.6125 g, 3.3 mmol). Themixture was allowed to stir a room temperature for 20 h. The solvent wasevaporated. The residue was chromatographed on silica gel (eluted with20% EtOAc in hexane) to give the title compound.

¹ H NMR (250 MHz, CDCl₃) δ 2.35 (d, 6H), 3.65 (s, 2H), 3.75 (s, 3H),4.0(s, 2H), 6.75 (s, 1H), 6.82 (d, 2H, J=6 Hz), 7.15 (d, 2H, J=6 Hz).

EXAMPLE 46 Preparation of4-hydroxy-7-chloro-3,5-dimethyl-2-(4'-methoxyphenylmethyl)benzofuran(178)

To a solution of (177) (Example 45) (0.106 g, 0.3 mmol) in 5 mL ethanolwas added sodium borohydride (0.111 g, 3 mmol). The mixture was refluxedfor 1 h, cooled and poured into cold dilute HCl (1N). Extraction withethyl acetate, followed by chromatography of the concentrated organicextract gave the title compound.

¹ H NMR (250 MHz, CDCl₃) δ 2.25 (S, 3H), 2.38 (S, 3H), 3.78 (S, 3H),4.04 (S, 2H), 4.78 (S, 1H), 6.85 (d, 2H, J=6 Hz), 6.92 (S, 1H), 7.18 (d,2H, J=6 Hz).

Anal. Calcd. for C₁₈ H₁₇ ClO₃ : C, 68.24; H, 5.37; Cl, 11.21. Found: C,68.14; H, 5.66; Cl, 11.16.

EXAMPLE 47 Preparation of4-hydroxy-5-ethoxymethyl-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(182)

A mixture of (177) (Example 45) (0.1 g, 0.28 mmol), ethyl bromide, (1mL) and ethanol (5 mL) was refluxed for 6 h. The solvent was evaporated,the residue was chromatographed on preparative tlc to give the titlecompound.

¹ H NMR (250 MHz, CDCl₃) δ 1.2 (t, 3H), 2.3 (S, 3H), 3.55 (q, 2H), 3.7(s, 3H), 3.95 (s, 2H), 4.5 (s, 2H), 6.70 (S, 1H), 6.75 (d, 2H, J=6 Hz),7.1 (d, 2H, J=6 Hz)

Mass Spec. (M⁺) 360 m/e .

EXAMPLE 48 Preparation of5-allyl-4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(179)

To a solution of4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran (164)(Example 44) (1.5 g, 5 mmol) in 30 mL acetone was added potassiumcarbonate (690 mg, 5 mmol) amd allyl bromide (605 mg, 5 mmol). Themixture was refluxed for 20 h, then filtered through celite aftercooling to room temperature. Concentration of the filtrate gave 1.94 gof the 4-allyloxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuranas a light brown oil. The crude material was refluxed in 8 mLo-dichlorobenzene for 6 h. Evaporation of the solvent followed bychromatography gave the title compound as a white solid, mp 90°-93° C.

¹ H NMR (250 MHz, CDCl₃) δ 2.35 (S, 3H), 3.40 (d, 2H, J=6 Hz), 3.78 (S,3H), 4.0 (S, 2H), 5.23 (m, 2H), 6.00 (m, 2H), 6.84 (d, 2H, J=7.5 Hz),6.91 (S, 1H), 7.18 (d, 2H, J=7 Hz).

Anal. Calcd. for C₂₀ H₁₉ ClO₃ : C, 70.07; H, 5.59; Cl, 10 34. Found: C,69.81; H, 5.90; Cl, 10.44.

EXAMPLE 49 Preparation of4-hydroxy-5-(3-hydroxy)propyl-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(180)

To a solution of (179) (Example 48) (342 mg, 1 mmol) in 10 mLdichloromethane was added t-butyldimethylchlorosilane (180 mg, 1.2mmol), triethylamine (202 mg, 2 mmol), dimethylaminopyridine (61 mg, 0.5mmol). The mixture was allowed to stir at room temperature for 20 h.Dilute HCl was added and the mixture was extracted with ethyl acetate.The extracts were dried (anhyd. MgSO₄) and chromatography of theconcentrated extract gave 410 mg of the silylated phenol. A solution ofthe latter product in dry THF (5 mL) was cooled to -78° C. and asolution of borane in THF (1M, 2mL) was added. The mixture was allowedto stir at -78° C. for 1 h, warmed to room temperature and stirred for 1h. Trimethylamine N-oxide (684 mg, 6 mmol) was added. The mixture wasrefluxed for 3 h, chromatography of the cooled mixture gave 400 mg ofthe corresponding alcohol. Treatment of the silylated phenol alcoholwith tetra-n-butyl ammonium fluoride in THF gave the title compound(180), mp 133°-136° C.

¹ H NMR (250 MHz, CDCl₃) δ 1.89 (m, 2H), 2.38 (S, 3H), 2.81 (m, 2H),3.66 (m, 2H), 3.78 (s, 3H), 4.01 (S, 2H), 6.83 (d, 2H, J=7 Hz), 6.89 (S,1H), 7.18 (d, 2H, J=7 Hz).

Anal Calcd. for C₂₀ H₂₁ ClO₄ : C, 66.57; H, 5.87; Cl, 9.83. Found: C,66.50; H, 5.70; Cl, 9.80.

EXAMPLE 50 Preparation of4-hydroxy-5-(2-carboxy)ethyl-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(181)

To a solution of the silyated phenol derivative of (180) (Example 49)(400 mg, 0.84 mmol) in 10 mL acetone was added dropwise at 0° C. theJones reagent. The reaction was monitored by tlc. The crude silylatedacid after workup was treated with tetra-n-butyl ammonium fluoride asdescribed before. The title compound was isolated by preparative tlc, mp149°-151° C.

¹ H NMR (250 MHz, CDCl₃) δ 2.35 (S, 3H), 2.85 (m, 4H), 3.78 (S, 3H),4.00 (S, 2H), 6.82 (d, 2H, J=7 Hz), 6.87 (S, 1H), 7.16 (d, 2H, J=7 Hz).

EXAMPLE 517-Chloro-4-hydroxy-2-(4'-methoxyphenylmethyl)-5-propylbenzofuran (166)(a) Preparation of 2-chloro-4-propyl-1,5-dihydroxybenzene

To a solution of 5-chloro-3-propyl-2,6-dihydroxyacetophenone (Example23, Step a) (5 g, 32 mmol) in 50 mL acetic acid was added 50 mL hydrogenbromide. The mixture was refluxed for 5 h. Water was added and themixture was extracted with ethyl acetate. Chromatography of theconcentrated organic extract gave the title product.

(b) Preparation of 3-chloro-5-propyl-2,6-dihydroxybenzaldehyde

To a solution of 2-chloro-4-propyl-1,5-dihydroxybenzene (from Step a,243 mg, 1.3 mmol) in 10 mL trifluoroacetic acid was added 1 g ofhexamine. The mixture was refluxed for 20 h. Water was added and themixture was extracted with ethyl acetate. Chromatography of theconcentrated organic extracts gave the title compound.

H¹ NMR δ 1.95 (t, 3H), 1.6 (m, 2H), 2.55 (t, 2H), 7.3 (s, 1H), 10.45 (s,1H).

(c) The title compound was prepared according to the methodology ofExample 42 using the starting material from Step b above, mp 88° C.

¹ H NMR (90 MHz, CDCl₃) δ 0.9 (t, 3H, J=7 Hz) 1.4 (sextet, 2H, J=7 Hz)2.55 (t, 2H, J=7 Hz) 3.65 (s, 3H) 3.9 (s, 2H) 6.55 (s, 1H) 6.8 (d, 2H,J=9 Hz) 6.8 (s, 1H) 7.15 (d, 2H, J=9 Hz) 7.18 (s, 1H).

Mass Spec (M⁺) 330 m/e.

EXAMPLE 52 Preparation of7-Chloro-4-hydroxy-3-methyl-2-phenyl-5-propylbenzofuran (172) (a)Methyl-2-phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy) acetate

A solution of triphenylphosphine (9.7 g, 37 mmol) in tetrahydrofuran (50mL) was added dropwise to a mixture of5-chloro-2,6-dihydroxy-3-propyl-3-propylacetophenone (Example 23, Stepa) (5.0 g, 22 mmol), methyl 2-hydroxy-2-phenylacetate (4.2 g, 25 mmol)and diethylazodicarboxylate (6.1 g, 37 mmol) in tetrahydrofuran (200 mL)at 0° C. The mixture was then stirred at room temperature for 1 hour,concentrated and the residue chromatographed on silica gel with 10%ethyl acetate in hexane to obtain the title compound, m.p. 65°-66° C.

Calcd. for C₂₀ H₂₁ ClO₅ : C, 63.74; H, 5.61; Cl, 9.40. Found: C, 63.63;H, 5.98; Cl, 9.50.

(b) 2-Phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy) acetic acid

A mixture of methyl2-phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy) acetate (Stepa) (6.2 g, 16 mmol), 10N sodium hydroxide (10 mL) and methanol (75 mL)was refluxed for 1.5 hours. The mixture was concentrated to remove mostof the methanol. The residue was dissolved in water (200 mL) andextracted with diethyl ether to remove neutral material. The aqueousphase was acidified with 6N HCl (100 mL) and extracted with diethylether. The ether extract was dried (MgSO₄), filtered and concentrated toobtain the title compound, m.p. 131°-133° C.

Calcd. for C₁₉ H₁₉ ClO₅ : C, 62,89; H, 5.27; Cl, 9.77. Found: C, 62.43;H, 5.52; Cl, 9.48.

(c) 4-acetoxy-7-chloro-3-methyl-2-phenyl-5-propylbenzofuran

A mixture of 2-phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy)acetic acid (Step b)(3.4 g, 9.3 mmol), anhydrous sodium acetate (6.8 g,82 mmol) and acetic anhydride (50 mL) was refluxed for 1 hour. Themixture was cooled, diluted with diethyl ether and the salts filteredoff. The filtrate was concentrated and the residue chromatographed onsilica gel with 10% ethyl acetate in hexane to obtain the titlecompound, m.p. 86°-87° C.

Calcd. for C₂₀ H₁₉ ClO₃ : C, 70.07; H, 5.58; Cl, 10.34. Found: C, 70.09;H, 6.03; Cl, 10.54.

(d) 7-chloro-4-hydroxy-3-methyl-2-phenyl-5-propylbenzofuran (172)

A mixture of 4-acetoxy-7-chloro-3-methyl-2-phenyl-5-propylbenzofuran(Step c) (1.5 g, 4.6 mmol), methanol (75 mL) and 3N sodium hydroxide (10mL) was heated to obtain a solution which was then stirred at roomtemperature for 2 hours. The mixture was acidified with 1N hydrochloricacid (100 mL) and extracted with diethyl ether. The ether extracts weredried (MgSO₄), filtered and concentrated. The residue was slurried withhexane, filtered and washed with hexane to obtain the title compound,m.p. 102°-104° C.

Calcd. for C₁₈ H₁₇ ClO₂ : C, 71.87; H, 5.69; Cl, 11.78. Found: C, 71.52;H, 6 10; Cl, 11 80.

EXAMPLE 53 Preparation of7-Chloro-4-hydroxy-3-methyl-2-(4'-methoxyphenylmethyl)-5-propylbenzothiophene(171) (a) O-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenyl)dimethylthiocarbamate

To a stirring mixture of 50% sodium hydride dispersion (2.1 g, 43 mmol)in dimethylformamide (100 mL) under nitrogen atmosphere and withice-water cooling was added 3-chloro-2,6-dihydroxy-5-propylacetophenone(Example 23, Step a) (10 g, 43 mmol). After stirring for one hour, asolution of dimethylthiocarbamoyl chloride (5.3 g, 43 mmol) indimethylformamide (25 mL) was added dropwise over 15 minutes. Themixture was then stirred at room temperature for 18 hours, poured intocold 1N HCl (75 mL) and extracted with diethyl ether. The ether layerwas backwashed twice with water, dried (MgSO₄), filtered, concentratedand chromatographed to obtain the title compound, m.p. 114°-116° C.

Calcd. for C₁₄ H₁₈ NSClO₃ : C, 53.24; H, 5.74; N, 4.43; S, 10.15; Cl,11.22. Found: C, 53.60; H, 5.81; N, 4.23; S, 10.03; Cl, 11.45.

(b) O-(2-acetyl-3-acetoxy-4-propyl-6-chlorophenyl) dimethylthiocarbamate

Acetyl chloride (1.9 g, 25 mmol) was added dropwise to an ice-coldstirring mixture of O-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenyl)dimethylthiocarbamate (6.3 g, 20 mmol) (Step a) and triethylamine (3.0g, 30 mmol) in tetrahydrofuran (50 mL) The mixture was stirred for 2hours and then diluted with water and diethyl ether. The organic layerwas separated, dried (MgSO₄), filtered and concentrated to obtain thetitle compound as an oil which crystallized on standing. The crystalswere slurried with hexane, filtered and dried to give the titlecompound, m.p. 86°-88° C.

Calcd. for C₁₆ H₂₀ NSClO₄ : C, 53.70; H, 5.63; N, 3.91; S, 8.95; Cl,9.90. Found: C, 53.88; H, 5.65; N, 3.72; S, 8.98; Cl, 10.03.

(c) S-(2-acetyl-3-acetoxy-4-propyl-6-chlorophenyl) dimethylthiocarbamate

A solution of O-(2-acetyl-3-acetoxy-4-propyl-6-chlorophenyl)dimethylthiocarbamate (Step b) (6.8 g, 19 mmol) in o-dichlorobenzene (25mL) was refluxed under nitrogen atmosphere for 30 hours. The mixture waschromatographed on silica gel, eluting with 20% ethyl acetate in tolueneto yield the title compound as an oil.

Calcd. for C₁₆ H₂₀ NSClO₄ : C, 53.70; H, 5.63; N, 3.91; S, 8.95; Cl,9.90. Found: C, 54.51; H, 5.99; N, 3.61; S, 8.94; Cl, 9.77.

(d) 5-chloro-2-hydroxy-6-mercapto-3-propylacetophenone

A solution of 5-(2-acetyl-3-acetoxy-4-propyl-6-chlorophenyl)dimethylthiocarbamate (Step c) (3.5 g, 9.8 mmol) in 1,2-dichloroethane(10 mL) was added dropwise over 2 minutes to a solution of 10equivalents of boron tribromide in 1,2-dichloroethane (122 mL of 0.8Molar). The mixture was brought to reflux for 1 hour as nitrogen waspassed over the system to expel hydrogen bromide. The mixture was cooledto 0°-5° C. and decomposed with H₂ O. The organic layer was separated,dried (MgSO₄), filtered, concentrated and chromatographed on silica geleluting with 30% ethyl acetate in hexane to obtain the title compound asan oil.

Mass Spec. (M⁺) 244 m/e.

(e)7-Chloro-4-hydroxy-3-methyl-2-(4'-methoxyphenylmethyl)-5-propylbenzothiophene(171)

The title compound was prepared using the methodology of Example 42,using the title compound of Step d for starting material, m.p. 80° C.

¹ H NMR (90 MHz), δ 0.98 (t, 3H, J=7 Hz) 1.65 (sextet, 2H, J=7 Hz) 2.6(s, m, 5H) 3.78 (s, 3 H) 4.18 (s, 2H) 5.15 (s, 1H) 6.8 (d, 2H, J=9 Hz)6.95 (s, 1H) 7.15 (d, 2H, J=9 Hz).

Mass Spec. (M⁺) 360 m/e.

What is claimed is:
 1. A compound of the formula ##STR24## wherein thesubstituents are selected from:

    ______________________________________                                               R.sup.3     Y.sup.2                                                    ______________________________________                                               OAc         OCH.sub.2 CO.sub.2 Et                                             OH          OCH.sub.2 CO.sub.2 H.                                      ______________________________________                                    


2. A pharmaceutical composition useful in inhibiting leukotrieneformation in mammals comprising an amount of a compound of claim 1effective as a leuketriene inhibitor and a pharmaceutically acceptablecarrier.
 3. A method of inhibiting leukotriene action in mammals whichcomprises administering to a mammal an effective amount of a compound ofclaim 1
 4. A method of treating or ameliorating allergic conditions,asthma, psoriasis, pain, infIammation, or cardiovascular conditions inmammals or inducing cytoprotection in mammals comprising administeringto a mammal in need of said treatment an effective amount of a compoundof claim 1.